Quinolines as FGFR kinase modulators

ABSTRACT

The invention relates to new quinoline derivative compounds of formula (I), to pharmaceutical compositions comprising said compounds, to processes for the preparation of said compounds and to the use of said compounds in the treatment of diseases, e.g. cancer.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/354,773 filed on Apr. 28, 2014, which is a national stage filingunder Section 371 of International Application No. PCT/GB2012/052666filed on Oct. 26, 2012, and published in English as WO 2013/061074 A1 onMay 2, 2013, and claims priority to British Application No. 1118652.5filed on Oct. 28, 2011 and to U.S. Provisional Application No.61/552,880 filed on Oct. 28, 2011. The entire disclosures of each of theprior applications are hereby incorporated herein by reference.

FIELD OF THE INVENTION

The invention relates to new quinoline derivative compounds, topharmaceutical compositions comprising said compounds, to processes forthe preparation of said compounds and to the use of said compounds inthe treatment of diseases, e.g. cancer.

SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided compoundsof formula (I):

including any tautomeric or stereochemically isomeric form thereof,whereinW is —N(R³)— or —C(R^(3a)R^(3b))—;each R² is independently selected from hydroxyl, halogen, cyano,C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, hydroxyhaloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, haloC₁₋₄ alkoxyC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl may optionally be substitutedwith one or two hydroxyl groups, hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl, R¹³,C₁₋₄alkyl substituted with R¹³, C₁₋₄alkyl substituted with —C(═O)—R¹³,C₁₋₄alkoxy substituted with R¹³, C₁₋₄alkoxy substituted with —C(═O)—R¹³,—C(═O)—R¹³, C₁₋₄alkyl substituted with —NR⁷R⁸, C₁₋₄alkyl substitutedwith —C(═O)—NR⁷R⁸, C₁₋₄alkoxy substituted with —NR⁷R⁸, C₁₋₄alkoxysubstituted with —C(═O)—NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸; or when two R²groups are attached to adjacent carbon atoms they may be taken togetherto form a radical of formula:—O—(C(R¹⁷)₂)_(p)—O—;—X—CH═CH—; or—X—CH═N—;

-   -   wherein R¹⁷ represents hydrogen or fluorine, p represents 1 or 2    -   and X represents O or S;        Y represents —CR¹⁸═N—OR¹⁹ or -E-D;        D represents a 3 to 12 ring membered monocyclic or bicyclic        carbocyclyl or a 3 to 12 ring membered monocyclic or bicyclic        heterocyclyl containing at least one heteroatom selected from N,        O or S, wherein said carbocyclyl and heterocyclyl may each be        optionally substituted by one or more (e.g. 1, 2 or 3) R¹        groups;        E represents a bond, —(CR²²R²³)_(n)—, C₂₋₄alkenediyl optionally        substituted with R²², C₂₋₄alkynediyl optionally substituted with        R²², —CO—(CR²²R²³)_(s)—, —(CR²²R²³)_(s)—CO—,        —NR²²—(CR²²R²³)_(s)—, —(CR²²R²³)_(s)—NR²²—, —O—(CR²²R²³)_(s)—,        —(CR²²R²³)_(s)—O—, —S(O)_(m)—(CR²²R²³)_(s)—,        —(CR²²R²³)_(s)—S(O)_(m)—, —(CR²²R²³)_(s)—CO—NR²²—(CR²²R²³)_(s)—        or —(CR²²R²³)—NR²²—CO—(CR²²R²³)_(s)—;        R¹ represents hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,        —C(═O)—O—C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl,        haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl,        C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be        substituted with one or two hydroxyl groups, —NR⁴R⁵, C₁₋₆alkyl        substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with        —NR⁴R⁵, —C(═O)—NR⁴R⁵, —C(═O)—C₁₋₆alkyl-NR⁴R⁵, C₁₋₆alkyl        substituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl,        —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted        with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with        —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with        —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with        —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with        —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with        —NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶,        —C(═O)—R⁶, C₁₋₆alkyl substituted with —C(═O)—R⁶,        hydroxyC₁₋₆alkyl substituted with R⁶, C₁₋₆alkyl substituted with        —Si(CH₃)₃, C₁₋₆alkyl substituted with —P(═O)(OH)₂ or C₁₋₆alkyl        substituted with —P(═O)(OC₁₋₆alkyl)₂;        R^(3a) represents —NR¹⁰R¹¹, hydroxyl, C₁₋₆alkoxy,        hydroxyC₁₋₆alkoxy, C₁₋₆alkoxy substituted with —NR¹⁰R¹¹,        C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl, haloC₁₋₆alkyl optionally        substituted with —O—C(═O)—C₁₋₆alkyl hydroxyC₁₋₆alkyl optionally        substituted with —O—C(═O)—C₁₋₆alkyl hydroxyC₂₋₆alkenyl,        hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₆alkyl,        C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkyl substituted with        —C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl,        C₁₋₆alkyl substituted with C₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—,        C₁₋₆alkyl substituted with C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl        substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein        each C₁₋₆alkyl may optionally be substituted with one or two        hydroxyl groups or with —O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl        substituted with C₁₋₆alkoxy, C₂₋₆alkynyl substituted with        C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ and optionally        substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with        —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹,        C₂₋₆alkenyl substituted with R⁹, C₂₋₆alkynyl substituted with        R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted        with —NR¹⁰R¹¹, C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl        substituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted        with one or two halogens and —NR¹⁰R¹¹,        —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with        —C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,        —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵,        C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl        substituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted        with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with        —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with        —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with        —NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with        —P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂;        R^(3b) represents hydrogen or hydroxyl; provided that if R^(3a)        represents —NR¹⁰R¹¹, then R^(3b) represents hydrogen; or        R^(3a) and R^(3b) are taken together to form ═O, to form ═NR¹⁰,        to form cyclopropyl together with the carbon atom to which they        are attached, to form ═CH—C₀₋₄alkyl substituted with R^(3c), or        to form

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining one heteroatom selected from N, O or S, said heteroatom notbeing positioned in alpha position of the double bond, wherein ring A isoptionally being substituted with cyano, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,H₂N—C₁₋₄alkyl, (C₁₋₄alkyl)NH—C₁₋₄alkyl, (C₁₋₄alkyl)₂N—C₁₋₄alkyl,haloC₁₋₄alkyl)NH—C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, —C(═O)—NH₂,—C(═O)—NH(C₁₋₄alkyl), —C(═O)—N(C₁₋₄alkyl)₂;R^(3c) represents hydrogen, hydroxyl, C₁₋₆alkoxy, R⁹, —NR¹⁰R¹¹, cyano,—C(═O)—C₁₋₆alkyl or —CH(OH)—C₁₋₆alkyl;R³ represents hydroxyl, C₁₋₆alkoxy, hydroxyC₁₋₆alkoxy, C₁₋₆alkoxysubstituted with —NR¹⁰R¹¹, C₁₋₆alkyl, C₂₋₆alkenyl, C₂₋₆alkynyl,haloC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₁₋₆alkyl optionally substituted with —O—C(═O)—C₁₋₆alkyl,hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl, hydroxyhaloC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkylsubstituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁹R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₅alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂;R⁴ and R⁵ each independently represent hydrogen, C₁₋₆alkyl, C₁₋₆alkylsubstituted with —NR¹⁴R¹⁵, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵,—C(═O)—NR¹⁴R¹⁵, —C(═O)—O—C₁₋₆alkyl, —C(═O)—R¹³, C₁₋₆alkyl substitutedwith —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵, R¹³ or C₁₋₆alkyl substituted with R¹³;R⁶ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O or S; said C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to7-membered monocyclic heterocyclyl, optionally and each independentlybeing substituted by 1, 2, 3, 4 or 5 substituents, each substituentindependently being selected from cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl,hydroxyl, carboxyl, hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl,C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl or C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵;R⁷ and R⁸ each independently represent hydrogen, C₁₋₆alkyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl orC₁₋₆alkoxyC₁₋₆alkyl;R⁹ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, naphthyl, or 3to 12 membered monocyclic or bicyclic heterocyclyl containing at leastone heteroatom selected from N, O or S, said C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, phenyl, naphthyl, or 3 to 12 membered monocyclic orbicyclic heterocyclyl each optionally and each independently beingsubstituted with 1, 2, 3, 4 or 5 substituents, each substituentindependently being selected from ═O, C₁₋₄alkyl, hydroxyl, carboxyl,hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkylsubstituted with C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkyl-C(═O)—,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl may optionally be substitutedwith one or two hydroxyl groups, halogen, haloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkyl substitutedwith —NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkylsubstituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with—NH—S(═O)₂—C₁₋₄alkyl, C₁₋₄alkyl substituted with—NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with R¹³, phenyl optionallysubstituted with R¹⁶, phenylC₁₋₆alkyl wherein the phenyl is optionallysubstituted with R¹⁶, a 5 or 6-membered aromatic monocyclic heterocyclylcontaining at least one heteroatom selected from N, O or S wherein saidheterocyclyl is optionally substituted with R¹⁶;or when two of the substituents of R⁹ are attached to the same atom,they may be taken together to form a 4 to 7-membered saturatedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O or S;R¹⁰ and R¹¹ each independently represent hydrogen, carboxyl, C₁₋₆alkyl,cyanoC₁₋₅alkyl, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups,R⁶, C₁₋₆alkyl substituted with R⁶, —C(═O)—R⁶, —C(═O)—C₁₋₆alkyl,—C(═O)-hydroxyC₁₋₆alkyl, —C(═O)-haloC₁₋₆alkyl,—C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with —Si(CH₃)₃,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with carboxyl, orC₁₋₆alkyl substituted with NH—S(═O)₂—NR¹⁴R¹⁵;R¹² represents hydrogen or C₁₋₄alkyl optionally substituted withC₁₋₄alkoxy;R¹³ represents C₃₋₈cycloalkyl or a saturated 4 to 6-membered monocyclicheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said C₃₋₈cycloalkyl or monocyclic heterocyclyl is optionallysubstituted with 1, 2 or 3 substituents each independently selected fromhalogen, hydroxyl, C₁₋₆alkyl, haloC₁₋₆alkyl, ═O, cyano,—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxy, or —NR¹⁴R¹⁵;R¹⁴ and R¹⁵ each independently represent hydrogen, or haloC₁₋₄alkyl, orC₁₋₄alkyl optionally substituted with a substituent selected fromhydroxyl, C₁₋₄alkoxy, amino or mono- or di(C₁₋₄alkyl)amino;R¹⁶ represents hydroxyl, halogen, cyano, C₁₋₄alkoxy, —NR¹⁴R¹⁵ or—C(═O)NR¹⁴R¹⁵;R¹⁸ represents hydrogen, C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₄alkylsubstituted with C₃₋₈ cycloalkyl;R¹⁹ represents hydrogen; C₁₋₆ alkyl; C₃₋₈ cycloalkyl; C₁₋₆alkylsubstituted with —O—R²⁰; —(CH₂)_(r)—CN; —(CH₂)_(r)—CONR²⁰R²¹;(CH₂)_(r)—NR²⁰R²¹; —(CH₂)_(r1)—NR²⁰COR²¹;—(CH₂)_(r1)—NR²⁰—(CH₂)_(s)—SO₂—R²¹; —(CH₂)_(r1)—NH—SO₂—NR²⁰R²¹;—(CH₂)_(r1)—NR²⁰CO₂R²¹; —(CH₂)_(r)—SO₂NR²⁰R²¹; phenyl optionallysubstituted with 1, 2, 3, 4 or 5 substituents each independentlyselected from halogen, C₁₋₄alkyl, C₁₋₄alkyloxy, cyano or amino; a 5- or6-membered aromatic monocyclic heterocycle containing at least oneheteroatom selected from N, O or S, said heterocycle being optionallysubstituted with 1, 2, 3 or 4 substituents each independently selectedfrom halogen, C₁₋₄alkyl, C₁₋₄alkyloxy, cyano or amino; wherein said C₁₋₆alkyl and C₃₋₈ cycloalkyl, may be optionally substituted by one or moreR²⁰ groupsR²⁰ and R²¹ independently represent hydrogen, C₁₋₆ alkyl,hydroxyC₁₋₆alkyl, —(CH₂)_(n)—O—C₁₋₆alkyl, or when attached to a nitrogenatom R²⁰ and R²¹ can be taken together to form with the nitrogen atom towhich they are attached a monocyclic saturated 4, 5 or 6-membered ringwhich optionally contains a further heteroatom selected from 0, S or N;R²² and R²³ independently represent hydrogen, C₁₋₆ alkyl, orhydroxyC₁₋₆alkyl;m independently represents an integer equal to 0, 1 or 2;n independently represents an integer equal to 0, 1, 2, 3 or 4;s independently represents an integer equal to 0, 1, 2, 3 or 4;r independently represent an integer equal to 1, 2, 3, or 4;r1 independently represent an integer equal to 2, 3 or 4;the N-oxides thereof, the pharmaceutically acceptable salts thereof orthe solvates thereof.

WO2006/092430, WO2008/003702, WO01/68047, WO2005/007099, WO2004/098494,WO2009/141386, WO 2004/030635, WO 2008/141065, WO 2011/026579, WO2011/028947, WO 2007/003419, WO 00/42026, WO2011/146591 andWO2011/135376 which each disclose a series of heterocyclyl derivatives.

DETAILED DESCRIPTION OF THE INVENTION

Unless the context indicates otherwise, references to formula (I) in allsections of this document (including the uses, methods and other aspectsof the invention) include references to all other sub-formula (e.g. Ia),sub-groups, preferences, embodiments and examples as defined herein.

The prefix “C_(x-y)” (where x and y are integers) as used herein refersto the number of carbon atoms in a given group. Thus, a C₁₋₆alkyl groupcontains from 1 to 6 carbon atoms, a C₃₋₆cycloalkyl group contains from3 to 6 carbon atoms, a C₁₋₄alkoxy group contains from 1 to 4 carbonatoms, and so on.

The term ‘halo’ or ‘halogen’ as used herein refers to a fluorine,chlorine, bromine or iodine atom.

The term ‘C₁₋₄alkyl’, or ‘C₁₋₆alkyl’ as used herein as a group or partof a group refers to a linear or branched saturated hydrocarbon groupcontaining from 1 to 4 or 1 to 6 carbon atoms. Examples of such groupsinclude methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or hexyl and thelike.

The term ‘C₂₋₄alkenyl’ or ‘C₂₋₆alkenyl’ as used herein as a group orpart of a group refers to a linear or branched hydrocarbon groupcontaining from 2 to 4 or 2 to 6 carbon atoms and containing a carboncarbon double bond.

The term ‘C₂₋₄alkenediyl’ used herein as a group or part of a grouprefers to a linear or branched bivalent hydrocarbon group containingfrom 2 to 4 carbon atoms and containing a carbon carbon double bond.

The term ‘C₂₋₄alkynyl’ or ‘C₂₋₆alkynyl’ as used herein as a group orpart of a group refers to a linear or branched hydrocarbon group havingfrom 2 to 4 or 2 to 6 carbon atoms and containing a carbon carbon triplebond.

The term ‘C₁₋₄alkoxy’ or ‘C₁₋₆alkoxy’ as used herein as a group or partof a group refers to an —O—C₁₋₄alkyl group or an —O—C₁₋₆alkyl groupwherein C₁₋₄alkyl and C₁₋₆alkyl are as defined herein. Examples of suchgroups include methoxy, ethoxy, propoxy, butoxy, and the like.

The term ‘C₁₋₄alkoxyC₁₋₄alkyl’ or ‘C₁₋₆alkoxyC₁₋₆alkyl’ as used hereinas a group or part of a group refers to a C₁₋₄alkyl-O—C₁₋₄alkyl group ora C₁₋₆alkyl-O—C₁₋₆alkyl group wherein C₁₋₄alkyl and C₁₋₆alkyl are asdefined herein. Examples of such groups include methoxyethyl,ethoxyethyl, propoxymethyl, butoxypropyl, and the like.

The term ‘C₃₋₈cycloalkyl’ as used herein refers to a saturatedmonocyclic hydrocarbon ring of 3 to 8 carbon atoms. Examples of suchgroups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl and the like.

The term ‘C₃₋₈cycloalkenyl’ as used herein refers to a monocyclichydrocarbon ring of 3 to 8 carbon atoms having a carbon carbon doublebond.

The term ‘hydroxyC₁₋₄alkyl’ or ‘hydroxyC₁₋₆alkyl’ as used herein as agroup or part of a group refers to a C₁₋₄alkyl or C₁₋₆alkyl group asdefined herein wherein one or more than one hydrogen atom is replacedwith a hydroxyl group. The terms ‘hydroxyC₁₋₄alkyl’ or‘hydroxyC₁₋₆alkyl’ therefore include monohydroxyC₁₋₄alkyl,monohydroxyC₁₋₆alkyl and also polyhydroxyC₁₋₄alkyl andpolyhydroxyC₁₋₆alkyl. There may be one, two, three or more hydrogenatoms replaced with a hydroxyl group, so the hydroxyC₁₋₄alkyl orhydroxyC₁₋₆alkyl may have one, two, three or more hydroxyl groups.Examples of such groups include hydroxymethyl, hydroxyethyl,hydroxypropyl and the like.

The term ‘haloC₁₋₄alkyl’ or ‘haloC₁₋₆alkyl’ as used herein as a group orpart of a group refers to a C₁₋₄alkyl or C₁₋₆alkyl group as definedherein wherein one or more than one hydrogen atom is replaced with ahalogen. The term ‘haloC₁₋₄alkyl’ or ‘haloC₁₋₆alkyl’ therefore includemonohaloC₁₋₄alkyl, monohaloC₁₋₆alkyl and also polyhaloC₁₋₄alkyl andpolyhaloC₁₋₆alkyl. There may be one, two, three or more hydrogen atomsreplaced with a halogen, so the haloC₁₋₄alkyl or haloC₁₋₆alkyl may haveone, two, three or more halogens. Examples of such groups includefluoroethyl, fluoromethyl, trifluoromethyl or trifluoroethyl and thelike.

The term ‘hydroxyhaloC₁₋₄alkyl’ or ‘hydroxyhaloC₁₋₆alkyl’ as used hereinas a group or part of a group refers to a C₁₋₄alkyl or C₁₋₆alkyl groupas defined herein wherein one or more than one hydrogen atom is replacedwith a hydroxyl group and one or more than one hydrogen atom is replacedwith a halogen. The term ‘hydroxyhaloC₁₋₄alkyl’ or‘hydroxyhaloC₁₋₆alkyl’ therefore refers to a C₁₋₄alkyl or C₁₋₆alkylgroup wherein one, two, three or more hydrogen atoms are replaced with ahydroxyl group and one, two, three or more hydrogen atoms are replacedwith a halogen.

The term ‘hydroxyC₁₋₄alkoxy’ or ‘hydroxyC₁₋₆alkoxy’ as used herein as agroup or part of a group refers to an —O—C₁₋₄alkyl group or an—O—C₁₋₆alkyl group wherein the C₁₋₄alkyl and C₁₋₆alkyl group is asdefined above and one or more than one hydrogen atom of the C₁₋₄alkyl orC₁₋₆alkyl group is replaced with a hydroxyl group. The term‘hydroxyC₁₋₄alkoxy’ or ‘hydroxyC₁₋₆alkoxy’ therefore includemonohydroxyC₁₋₄alkoxy, monohydroxyC₁₋₆alkoxy and alsopolyhydroxyC₁₋₄alkoxy and polyhydroxyC₁₋₆alkoxy. There may be one, two,three or more hydrogen atoms replaced with a hydroxyl group so thehydroxyC₁₋₄alkoxy or hydroxyC₁₋₆alkoxy may have one, two, three or morehydroxyl groups. Examples of such groups include hydroxymethoxy,hydroxyethoxy, hydroxypropoxy and the like.

The term ‘haloC₁₋₄alkoxy’ or ‘haloC₁₋₆alkoxy’ as used herein as a groupor part of a group refers to a —O—C₁₋₄alkyl group or a —O—C₁₋₆ alkylgroup as defined herein wherein one or more than one hydrogen atom isreplaced with a halogen. The terms ‘haloC₁₋₄alkoxy’ or ‘haloC₁₋₆alkoxy’therefore include monohaloC₁₋₄alkoxy, monohaloC₁₋₆alkoxy and alsopolyhaloC₁₋₄alkoxy and polyhaloC₁₋₆alkoxy. There may be one, two, threeor more hydrogen atoms replaced with a halogen, so the haloC₁₋₄alkoxy orhaloC₁₋₆alkoxy may have one, two, three or more halogens. Examples ofsuch groups include fluoroethyloxy, difluoromethoxy or trifluoromethoxyand the like.

The term ‘hydroxyhaloC₁₋₄alkoxy’ as used herein as a group or part of agroup refers to an —O—C₁₋₄alkyl group wherein the C₁₋₄alkyl group is asdefined herein and wherein one or more than one hydrogen atom isreplaced with a hydroxyl group and one or more than one hydrogen atom isreplaced with a halogen. The term ‘hydroxyhaloC₁₋₄alkoxy’ thereforerefers to a —O—C₁₋₄alkyl group wherein one, two, three or more hydrogenatoms are replaced with a hydroxyl group and one, two, three or morehydrogen atoms are replaced with a halogen.

The term ‘haloC₁₋₄alkoxyC₁₋₄alkyl’ as used herein as a group or part ofa group refers to a C₁₋₄alkyl-O—C₁₋₄alkyl group wherein C₁₋₄alkyl is asdefined herein and wherein in one or both of the C₁₋₄alkyl groups one ormore than one hydrogen atom is replaced with a halogen. The term‘haloC₁₋₄alkoxyC₁₋₄alkyl’ therefore refers to a C₁₋₄alkyl-O—C₁₋₄alkylgroup wherein in one or both of the C₁₋₄alkyl groups one, two, three ormore hydrogen atoms are replaced with a halogen and wherein C₁₋₄alkyl isas defined herein. Preferably, in one of the C₁₋₄alkyl groups one ormore than one hydrogen atom is replaced with a halogen. Preferably,haloC₁₋₄alkoxyC₁₋₄alkyl means C₁₋₄alkyl substituted with haloC₁₋₄alkoxy.

The term ‘hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl’ as used herein refers to aC₁₋₄alkyl-O—C₁₋₄alkyl group wherein C₁₋₄alkyl is as defined herein andwherein in one or both of the C₁₋₄alkyl groups one or more than onehydrogen atom is replaced with a hydroxyl group and one or more than onehydrogen atom is replaced with a halogen. The terms‘hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl’ therefore refers to aC₁₋₄alkyl-O—C₁₋₄alkyl group wherein in one or both of the C₁₋₄alkylgroups one, two, three or more hydrogen atoms are replaced with ahydroxyl group and one, two, three or more hydrogen atoms are replacedwith a halogen and wherein C₁₋₄alkyl is as defined herein.

The term ‘hydroxyC₂₋₆alkenyl’ as used herein refers to a C₂₋₆alkenylgroup wherein one or more than one hydrogen atom is replaced with ahydroxyl group and wherein C₂₋₆alkenyl is as defined herein.

The term ‘hydroxyC₂₋₆alkynyl’ as used herein refers to a C₂₋₆alkynylgroup wherein one or more than one hydrogen atom is replaced with ahydroxyl group and wherein C₂₋₆alkynyl is as defined herein.

The term phenylC₁₋₆alkyl as used herein refers to a C₁₋₆alkyl group asdefined herein which is substituted with one phenyl group.

The term cyanoC₁₋₄alkyl or cyanoC₁₋₆alkyl as used herein refers to aC₁₋₄alkyl or C₁₋₆alkyl group as defined herein which is substituted withone cyano group.

The term “heterocyclyl” as used herein shall, unless the contextindicates otherwise, include both aromatic and non-aromatic ringsystems. Thus, for example, the term “heterocyclyl group” includeswithin its scope aromatic, non-aromatic, unsaturated, partiallysaturated and fully saturated heterocyclyl ring systems. In general,unless the context indicates otherwise, such groups may be monocyclic orbicyclic and may contain, for example, 3 to 12 ring members, moreusually 5 to 10 ring members. Reference to 4 to 7 ring members include4, 5, 6 or 7 atoms in the ring and reference to 4 to 6 ring membersinclude 4, 5, or 6 atoms in the ring. Examples of monocyclic groups aregroups containing 3, 4, 5, 6, 7 and 8 ring members, more usually 3 to 7,and preferably 5, 6 or 7 ring members, more preferably 5 or 6 ringmembers. Examples of bicyclic groups are those containing 8, 9, 10, 11and 12 ring members, and more usually 9 or 10 ring members. Wherereference is made herein to heterocyclyl groups, the heterocyclyl ringcan, unless the context indicates otherwise, be optionally substituted(i.e. unsubstituted or substituted) by one or more substituents asdiscussed herein.

The heterocyclyl groups can be heteroaryl groups having from 5 to 12ring members, more usually from 5 to 10 ring members. The term“heteroaryl” is used herein to denote a heterocyclyl group havingaromatic character. The term “heteroaryl” embraces polycyclic (e.g.bicyclic) ring systems wherein one or more rings are non-aromatic,provided that at least one ring is aromatic. In such polycyclic systems,the group may be attached by the aromatic ring, or by a non-aromaticring.

Examples of heteroaryl groups are monocyclic and bicyclic groupscontaining from five to twelve ring members, and more usually from fiveto ten ring members. The heteroaryl group can be, for example, a fivemembered or six membered monocyclic ring or a bicyclic structure formedfrom fused five and six membered rings or two fused six membered rings,or two fused five membered rings. Each ring may contain up to about fiveheteroatoms typically selected from nitrogen, sulphur and oxygen.Typically the heteroaryl ring will contain up to 4 heteroatoms, moretypically up to 3 heteroatoms, more usually up to 2, for example asingle heteroatom. In one embodiment, the heteroaryl ring contains atleast one ring nitrogen atom. The nitrogen atoms in the heteroaryl ringscan be basic, as in the case of an imidazole or pyridine, or essentiallynon-basic as in the case of an indole or pyrrole nitrogen. In generalthe number of basic nitrogen atoms present in the heteroaryl group,including any amino group substituents of the ring, will be less thanfive.

Examples of five membered heteroaryl groups include but are not limitedto pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole,oxatriazole, isoxazole, thiazole, thiadiazole, isothiazole, pyrazole,triazole and tetrazole groups.

Examples of six membered heteroaryl groups include but are not limitedto pyridine, pyrazine, pyridazine, pyrimidine and triazine.

A bicyclic heteroaryl group may be, for example, a group selected from:

-   -   a) a benzene ring fused to a 5- or 6-membered ring containing 1,        2 or 3 ring heteroatoms;    -   b) a pyridine ring fused to a 5- or 6-membered ring containing        0, 1, 2 or 3 ring heteroatoms;    -   c) a pyrimidine ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   d) a pyrrole ring fused to a 5- or 6-membered ring containing 0,        1, 2 or 3 ring heteroatoms;    -   e) a pyrazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   f) an imidazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   g) an oxazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   h) an isoxazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   i) a thiazole ring fused to a 5- or 6-membered ring containing        0, 1 or 2 ring heteroatoms;    -   j) an isothiazole ring fused to a 5- or 6-membered ring        containing 0, 1 or 2 ring heteroatoms;    -   k) a thiophene ring fused to a 5- or 6-membered ring containing        0, 1, 2 or 3 ring heteroatoms;    -   l) a furan ring fused to a 5- or 6-membered ring containing 0,        1, 2 or 3 ring heteroatoms;    -   m) a cyclohexyl ring fused to a 5- or 6-membered ring containing        1, 2 or 3 ring heteroatoms; and    -   n) a cyclopentyl ring fused to a 5- or 6-membered ring        containing 1, 2 or 3 ring heteroatoms.

Particular examples of bicyclic heteroaryl groups containing a fivemembered ring fused to another five membered ring include but are notlimited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) andimidazoimidazole (e.g. imidazo[1,2-a]imidazole).

Particular examples of bicyclic heteroaryl groups containing a sixmembered ring fused to a five membered ring include but are not limitedto benzofuran, benzothiophene, benzimidazole, benzoxazole,isobenzoxazole, benzisoxazole, benzthiazole, benzisothiazole,isobenzofuran, indole, isoindole, indolizine, indoline, isoindoline,purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g.pyrazolo[1,5-a]pyrimidine), triazolopyrimidine (e.g.[1,2,4]triazolo[1,5-a]pyrimidine), benzodioxole, imidazopyridine andpyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine) groups.

Particular examples of bicyclic heteroaryl groups containing two fusedsix membered rings include but are not limited to quinoline,isoquinoline, chroman, thiochroman, chromene, isochromene, chroman,isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine,pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine,naphthyridine and pteridine groups.

Examples of polycyclic heteroaryl groups containing an aromatic ring anda non-aromatic ring include, tetrahydroisoquinoline,tetrahydroquinoline, dihydrobenzthiene, dihydrobenzfuran,2,3-dihydro-benzo[1,4]dioxine, benzo[1,3]dioxole,4,5,6,7-tetrahydrobenzofuran, tetrahydrotriazolopyrazine (e.g.5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine), indoline and indanegroups.

A nitrogen-containing heteroaryl ring must contain at least one ringnitrogen atom. Each ring may, in addition, contain up to about fourother heteroatoms typically selected from nitrogen, sulphur and oxygen.Typically the heteroaryl ring will contain up to 3 heteroatoms, forexample 1, 2 or 3, more usually up to 2 nitrogens, for example a singlenitrogen. The nitrogen atoms in the heteroaryl rings can be basic, as inthe case of an imidazole or pyridine, or essentially non-basic as in thecase of an indole or pyrrole nitrogen. In general the number of basicnitrogen atoms present in the heteroaryl group, including any aminogroup substituents of the ring, will be less than five.

Examples of nitrogen-containing heteroaryl groups include, but are notlimited to, pyridyl, pyrrolyl, imidazolyl, oxazolyl, oxadiazolyl,thiadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl,furazanyl, pyrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl,triazolyl (e.g., 1,2,3-triazolyl, 1,2,4-triazolyl), tetrazolyl,quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, benzisoxazole,benzthiazolyl and benzisothiazole, indolyl, 3H-indolyl, isoindolyl,indolizinyl, isoindolinyl, purinyl (e.g., adenine [6-aminopurine],guanine [2-amino-6-hydroxypurine]), indazolyl, quinolizinyl,benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl,quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl.

Examples of nitrogen-containing polycyclic heteroaryl groups containingan aromatic ring and a non-aromatic ring includetetrahydroisoquinolinyl, tetrahydroquinolinyl, and indolinyl.

The term “non-aromatic group” embraces, unless the context indicatesotherwise, unsaturated ring systems without aromatic character,partially saturated and fully saturated heterocyclyl ring systems. Theterms “unsaturated” and “partially saturated” refer to rings wherein thering structure(s) contains atoms sharing more than one valence bond i.e.the ring contains at least one multiple bond e.g. a C═C, C≡C or N═Cbond. The term “fully saturated” refers to rings where there are nomultiple bonds between ring atoms. Saturated heterocyclyl groups includepiperidine, morpholine, thiomorpholine, piperazine. Partially saturatedheterocyclyl groups include pyrazolines, for example 2-pyrazoline and3-pyrazoline.

Examples of non-aromatic heterocyclyl groups are groups having from 3 to12 ring members, more usually 5 to 10 ring members. Such groups can bemonocyclic or bicyclic, for example, and typically have from 1 to 5heteroatom ring members (more usually 1, 2, 3 or 4 heteroatom ringmembers), usually selected from nitrogen, oxygen and sulphur. Theheterocyclyl groups can contain, for example, cyclic ether moieties(e.g. as in tetrahydrofuran and dioxane), cyclic thioether moieties(e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties(e.g. as in pyrrolidine), cyclic amide moieties (e.g. as inpyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ureas (e.g.as in imidazolidin-2-one) cyclic ester moieties (e.g. as inbutyrolactone), cyclic sulphones (e.g. as in sulpholane and sulpholene),cyclic sulphoxides, cyclic sulphonamides and combinations thereof (e.g.thiomorpholine).

Particular examples include morpholine, piperidine (e.g. 1-piperidinyl,2-piperidinyl, 3-piperidinyl and 4-piperidinyl), piperidone, pyrrolidine(e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), pyrrolidone,azetidine, pyran (2H-pyran or 4H-pyran), dihydrothiophene, dihydropyran,dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene,dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline,imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine,piperazone, piperazine, and N-alkyl piperazines such as N-methylpiperazine. In general, preferred non-aromatic heterocyclyl groupsinclude saturated groups such as piperidine, pyrrolidine, azetidine,morpholine, piperazine and N-alkyl piperazines.

In a nitrogen-containing non-aromatic heterocyclyl ring the ring mustcontain at least one ring nitrogen atom. The heterocylic groups cancontain, for example cyclic amine moieties (e.g. as in pyrrolidine),cyclic amides (such as a pyrrolidinone, piperidone or caprolactam),cyclic sulphonamides (such as an isothiazolidine 1,1-dioxide,[1,2]thiazinane 1,1-dioxide or [1,2]thiazepane 1,1-dioxide) andcombinations thereof.

Particular examples of nitrogen-containing non-aromatic heterocyclylgroups include aziridine, morpholine, thiomorpholine, piperidine (e.g.1-piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl),pyrrolidine (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl),pyrrolidone, dihydrothiazole, imidazoline, imidazolidinone, oxazoline,thiazoline, 6H-1,2,5-thiadiazine, 2-pyrazoline, 3-pyrazoline,pyrazolidine, piperazine, and N-alkyl piperazines such as N-methylpiperazine.

The heterocyclyl groups can be polycyclic fused ring systems or bridgedring systems such as the oxa- and aza analogues of bicycloalkanes,tricycloalkanes (e.g. adamantane and oxa-adamantane). For an explanationof the distinction between fused and bridged ring systems, see AdvancedOrganic Chemistry, by Jerry March, 4^(th) Edition, Wiley Interscience,pages 131-133, 1992.

The heterocyclyl groups can each be unsubstituted or substituted by oneor more substituent groups. For example, heterocyclyl groups can beunsubstituted or substituted by 1, 2, 3 or 4 substituents. Where theheterocyclyl group is monocyclic or bicyclic, typically it isunsubstituted or has 1, 2 or 3 substituents.

The term “carbocyclyl” as used herein shall, unless the contextindicates otherwise, include both aromatic and non-aromatic ringsystems. Thus, for example, the term “carbocyclyl group” includes withinits scope aromatic, non-aromatic, unsaturated, partially saturated andfully saturated carbocyclyl ring systems. In general, unless the contextindicates otherwise, such groups may be monocyclic or bicyclic and maycontain, for example, 3 to 12 ring members, more usually 5 to 10 ringmembers. Reference to 4 to 7 ring members include 4, 5, 6 or 7 atoms inthe ring and reference to 4 to 6 ring members include 4, 5, or 6 atomsin the ring. Examples of monocyclic groups are groups containing 3, 4,5, 6, 7 and 8 ring members, more usually 3 to 7, and preferably 5, 6 or7 ring members, more preferably 5 or 6 ring members. Examples ofbicyclic groups are those containing 8, 9, 10, 11 and 12 ring members,and more usually 9 or 10 ring members. Where reference is made herein tocarbocyclyl groups, the carbocyclyl ring can, unless the contextindicates otherwise, be optionally substituted (i.e. unsubstituted orsubstituted) by one or more substituents as discussed herein.

The term carbocyclyl comprises aryl, C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl.

The term aryl as used herein refers to carbocyclyl aromatic groupsincluding phenyl, naphthyl, indenyl, and tetrahydronaphthyl groups.

Whenever used hereinbefore or hereinafter that substituents can beselected each independently out of a list of numerous definitions, allpossible combinations are intended which are chemically possible.Whenever used hereinbefore or hereinafter that a particular substituentis further substituted with two or more groups, such as for examplehydroxyhaloC₁₋₄alkyl, hydroxyhaloC₁₋₄alkoxy, all possible combinationsare intended which are chemically possible.

In one embodiment, Y represents —CR¹⁸═N—OR¹⁹. In particular wherein R¹⁸and R¹⁹ represent C₁₋₆alkyl.

In one embodiment, Y represents -E-D wherein E represents a bond.

In one embodiment, Y represents a 3 to 12 ring membered monocyclic orbicyclic carbocyclyl or a 3 to 12 ring membered monocyclic or bicyclicheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said carbocyclyl and heterocyclyl may each be optionallysubstituted by one or more (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, Y represents a 5 to 12 ring membered monocyclic orbicyclic carbocyclyl or a 5 to 12 ring membered monocyclic or bicyclicheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said carbocyclyl and heterocyclyl may each be optionallysubstituted by one or more (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, Y represents an aromatic 3 to 12, in particular anaromatic 5 to 12, ring membered monocyclic or bicyclic carbocyclyl or anaromatic 3 to 12, in particular an aromatic 5 to 12, ring memberedmonocyclic or bicyclic heterocyclyl containing at least one heteroatomselected from N, O or S, wherein said carbocyclyl and heterocyclyl mayeach be optionally substituted by one or more (e.g. 1, 2 or 3) R¹groups.

In one embodiment, Y represents an aromatic 3 to 12 (e.g. 5 to 10) ringmembered monocyclic or bicyclic carbocyclyl, wherein said carbocyclylmay be optionally substituted by one or more (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, Y represents phenyl or naphthyl, wherein said phenylor naphthyl may each be optionally substituted by one or more (e.g. 1, 2or 3) R¹ groups.

In one embodiment, Y represents a 5 to 12 ring membered monocyclic orbicyclic heterocyclyl containing at least one heteroatom selected fromN, O or S, wherein said heterocyclyl may each be optionally substitutedby one or more (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, Y represents an aromatic 5 to 12 ring memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O or S, wherein said heterocyclyl group may each be optionallysubstituted by one or more (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, Y represents a 5 or 6 ring membered monocyclicheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said heterocyclyl may each be optionally substituted by one ormore (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, Y represents an aromatic 5 or 6 ring memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O or S, wherein said heterocyclyl may each be optionally substitutedby one or more (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, Y represents a 5 ring membered monocyclicheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said heterocyclyl may each be optionally substituted by one ormore (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, Y represents a 5 ring membered monocyclic aromaticheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said heterocyclyl may each be optionally substituted by one ormore (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, Y represents pyrazolyl (e.g. pyrazol-4yl), whereinsaid pyrazolyl may each be optionally substituted by one or more (e.g.1, 2 or 3) R¹ groups.

In one embodiment, Y represents a 6 ring membered monocyclicheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said heterocyclyl may each be optionally substituted by one ormore (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, Y represents a 6 ring membered monocyclic aromaticheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said heterocyclyl may each be optionally substituted by one ormore (e.g. 1, 2 or 3) R¹ groups.

In one embodiment, Y represents a 12 ring membered bicyclic heterocyclylcontaining at least one heteroatom selected from N, O or S, wherein saidheterocyclyl may each be optionally substituted by one or more (e.g. 1,2 or 3) R¹ groups.

In one embodiment, Y represents a 12 ring membered bicyclic aromaticheterocyclyl containing at least one heteroatom selected from N, O or S,wherein said heterocyclyl may each be optionally substituted by one ormore (e.g. 1, 2 or 3) R¹ groups.

In one embodiment Y represents

wherein R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, C₁₋₆alkyl substituted with —NR⁴R⁵,C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; and eachR^(1a) is independently selected from hydrogen, C₁₋₄alkyl,hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted with amino or mono- ordi(C₁₋₄alkyl)amino or —NH(C₃₋₈cycloalkyl), cyanoC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more fluoroatoms. In one embodiment R^(1a) is independently selected from hydrogenand C₁₋₄alkyl. In one embodiment R^(1a) is hydrogen.

In one embodiment, Y represents

wherein R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, C₁₋₆alkyl substituted with —NR⁴R⁵,C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂.

In one embodiment, E represents a bond, C₂₋₄alkenediyl optionallysubstituted with R²², —CO—(CR²²R²³)_(s)—, —(CR²²R²³)_(s)—CO—,—NR²²—(CR²²R²³)_(s)—, —(CR²²R²³)_(s)—NR²²—, —O—(CR²²R²³)_(s)—,—(CR²²R²³)_(s)—CO—NR²²—(CR²²R²³)_(s)— or—(CR²²R²³)_(s)—NR²²—CO—(CR²²R²³)_(s)—.

In one embodiment, E represents a bond, C₂₋₄alkenediyl,—CO—(CR²²R²³)_(s)—, —(CR²²R²³)_(s)—CO—, —NR²²—(CR²²R²³)_(s)—,—(CR²²R²³)_(s)—NR²²—, —(CR²²R²³)_(s)—CO—NR²²—(CR²²R²³)_(s)— or—(CR²²R²³)_(s)—NR²²—CO—(CR²²R²³)_(s)—.

In one embodiment, E represents C₂₋₄alkenediyl, —CO—(CR²²R²³)_(s)—,—(CR²²R²³)_(s)—CO—, —NR²²—(CR²²R²³)_(s)—, —(CR²²R²³)_(s)—NR²²—,—(CR²²R²³)_(s)—CO—NR²²—(CR²²R²³)_(s)— or—(CR²²R²³)_(s)—NR²²—CO—(CR²²R²³)_(s)—.

In one embodiment, E represents a bond.

In one embodiment, W is —N(R³)—.

In one embodiment, W is —C(R^(3a)R^(3b))—.

In one embodiment, Y represents -E-D, wherein E is other than a bond.

In one embodiment, Y represents -E-D, wherein E is other than a bond andD represents any one of the following:

-   -   a 3 to 12 ring membered monocyclic or bicyclic carbocyclyl or a        3 to 12 ring membered monocyclic or bicyclic heterocyclyl        containing at least one heteroatom selected from N, O or S,        wherein said carbocyclyl and heterocyclyl may each be optionally        substituted by one or more (e.g. 1, 2 or 3) R¹ groups;    -   a 5 to 12 ring membered monocyclic or bicyclic carbocyclyl or a        5 to 12 ring membered monocyclic or bicyclic heterocyclyl        containing at least one heteroatom selected from N, O or S,        wherein said carbocyclyl and heterocyclyl may each be optionally        substituted by one or more (e.g. 1, 2 or 3) R¹ groups;    -   phenyl or naphthyl, wherein said phenyl or naphthyl may each be        optionally substituted by one or more (e.g. 1, 2 or 3) R¹        groups;    -   a 5 to 12 ring membered monocyclic or bicyclic heterocyclyl        containing at least one heteroatom selected from N, O or S,        wherein said heterocyclyl may each be optionally substituted by        one or more (e.g. 1, 2 or 3) R¹ groups;    -   a 5 or 6 ring membered monocyclic heterocyclyl containing at        least one heteroatom selected from N, O or S, wherein said        heterocyclyl may each be optionally substituted by one or more        (e.g. 1, 2 or 3) R¹ groups;    -   a 5 ring membered monocyclic heterocyclyl containing at least        one heteroatom selected from N, O or S, wherein said        heterocyclyl may each be optionally substituted by one or more        (e.g. 1, 2 or 3) R¹ groups;    -   a 5 ring membered monocyclic aromatic heterocyclyl containing at        least one heteroatom selected from N, O or S, wherein said        heterocyclyl group may each be optionally substituted by one or        more (e.g. 1, 2 or 3) R¹ groups;    -   a 6 ring membered monocyclic heterocyclyl containing at least        one heteroatom selected from N, O or S, wherein said        heterocyclyl may each be optionally substituted by one or more        (e.g. 1, 2 or 3) R¹ groups;    -   a 6 ring membered monocyclic aromatic heterocyclyl containing at        least one heteroatom selected from N, O or S, wherein said        heterocyclyl may each be optionally substituted by one or more        (e.g. 1, 2 or 3) R¹ groups;    -   a 12 ring membered bicyclic heterocyclyl containing at least one        heteroatom selected from N, O or S, wherein said heterocyclyl        may each be optionally substituted by one or more (e.g. 1, 2        or 3) R¹ groups;    -   a 12 ring membered bicyclic aromatic heterocyclyl containing at        least one heteroatom selected from N, O or S, wherein said        heterocyclyl may each be optionally substituted by one or more        (e.g. 1, 2 or 3) R¹ groups;

wherein R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, C₁₋₆alkyl substituted with —NR⁴R⁵,C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; and eachR^(1a) is independently selected from hydrogen, C₁₋₄alkyl,hydroxyC₁₋₄alkyl, C₁₋₄alkyl substituted with amino or mono- ordi(C₁₋₄alkyl)amino or —NH(C₃₋₈cycloalkyl), cyanoC₁₋₄alkyl,C₁₋₄alkoxyC₁₋₄alkyl, and C₁₋₄alkyl substituted with one or more fluoroatoms;

wherein R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl,hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups,C₁₋₆alkyl substituted with —NR⁴R⁶, C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂.

In one embodiment, D is other than pyrazolyl, in particular D ispiperidinyl, pyridinyl, phenyl, pyrolyl, imidazolyl, triazolyl,pyrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl, cyclopentyl,azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl,1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrolyl, pyrimidinyl,pyrolidinyl, thiadiazolyl, oxadiazolyl, said rings being optionallysubstituted. Said optional substituents may represent halo, cyano,C₁₋₆alkyl, C₁₋₆alkoxy, —C(═O)—O—C₁₋₆alkyl, hydroxyC₁₋₆alkyl, —NR⁴R⁵,C₁₋₆alkyl substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NR⁴R⁵, —C(═O)—NR⁴R⁵, —C(═O)—C₁₋₆alkyl-NR⁴R⁵, R⁶, C₁₋₆alkylsubstituted with R⁶.

In one embodiment, E is other than a bond and D is other than pyrazolyl,in particular D is piperidinyl, pyridinyl, phenyl, pyrrolyl, imidazolyl,triazolyl, pyrrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl,cyclopentyl, azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl,1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrolyl, pyrimidinyl,pyrrolidinyl, thiadiazolyl, oxadiazolyl, said rings being optionallysubstituted.

In one embodiment, E is a bond and D is optionally substituted4-pyrazolyl. In one embodiment, E is a bond and D is 4-pyrazolylsubstituted at the 1 position with C₁₋₆alkyl for example methyl.

In one embodiment, E is a bond and D is 1-pyrazolyl or 2-pyrazolyl, bothmay optionally be substituted.

In one embodiment, E is other than a bond and D is 1-pyrazolyl or2-pyrazolyl, both may optionally be substituted.

In one embodiment, E is other than a bond and D is optionallysubstituted pyrazolyl.

In one embodiment, E is a bond and D is optionally substitutedpyrazolyl.

In one embodiment, E is a bond and D is other than pyrazolyl, inparticular D is piperidinyl, pyridinyl, phenyl, pyrolyl, imidazolyl,triazolyl, pyrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl,cyclopentyl, azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl,1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrolyl, pyrimidinyl,pyrolidinyl, said rings being optionally substituted.

In one embodiment, E is a other than a bond and D is other thanpyrazolyl, in particular D is piperidinyl, pyridinyl, phenyl, pyrolyl,imidazolyl, triazolyl, pyrolopyridinyl, 1,3-benzodioxolyl, indolyl,thiazolyl, cyclopentyl, azetidinyl, morpholinyl, tetrazolyl, oxazolyl,piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrolyl,pyrimidinyl, pyrolidinyl, said rings being optionally substituted.

In one embodiment, E is a bond and D is an optionally substituted 6membered carbocycle, for example phenyl.

In one embodiment, E is a bond and D is an optionally substituted 6membered heterocycle, for example pyridyl.

In one embodiment, E is a bond and D is an optionally substituted 6membered partially saturated heterocycle, for example1,2,3,6-tetrahydropyridyl.

In one embodiment, E is a bond and D is an optionally substituted 6membered saturated heterocycle, for morpholinyl or piperidinyl. Optionalsubstituents are C(═O)—O—C₁₋₆alkyl.

In one embodiment, E is a bond and D is an optionally substitutedaromatic 6 membered heterocycle, for example pyridyl.

In one embodiment, E is a bond and D is an optionally substituted 5membered heterocycle.

In one embodiment, E is a bond and D is an optionally substitutedaromatic 5 membered heterocycle, for example pyrrolyl or pyrazolyl.Optional substituents are C₁₋₆alkyl.

In one embodiment R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, C₁₋₆alkyl substituted with —NR⁴R⁵,C₁₋₆alkyl substituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkylsubstituted with —C(═O)—R⁶, hydroxyC₁₋₆alkyl substituted with R⁶,C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with—P(═O)(OH)₂ or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂.

In one embodiment R¹ represents hydrogen, C₁₋₆alkyl, C₂₋₄alkenyl,hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups,C₁₋₆alkyl substituted with —NR⁴R⁵, C₁₋₆alkyl substituted with—C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substitutedwith —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,R⁶, C₁₋₆alkyl substituted with R⁶, C₁₋₆alkyl substituted with —C(═O)—R⁶,hydroxyC₁₋₆alkyl substituted with R⁶, or C₁₋₆alkyl substituted with—Si(CH₃)₃.

In one embodiment, R¹ represents hydrogen, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl or R⁶.

In one embodiment, R¹ represents hydrogen, C₁₋₆alkyl,—C(═O)—O—C₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl or R⁶.

In one embodiment R⁶ represents optionally substituted 4 to 7-memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O or S. In one embodiment R⁶ represents optionally substitutednon-aromatic 4 to 7-membered (e.g. 6 membered) monocyclic heterocyclylcontaining at least one heteroatom selected from N, O or S. In oneembodiment R⁶ represents tetrahydropyranyl.

In one embodiment, R¹ represents hydrogen, C₁₋₆alkyl (e.g methyl),hydroxyC₁₋₆alkyl (e.g. —CH₂CH₂OH), C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl (e.g. —CH₂CH₂—SO₂—CH₃) or optionally substitutednon-aromatic 4 to 7-membered (e.g. 6 membered) monocyclic heterocyclylcontaining at least one heteroatom selected from N, O or S (e.g.tetrahydropyranyl).

In one embodiment, R1 represents —C(═O)—O—C₁₋₆alkyl (e.g.—C(═O)—O—C(CH₃)₃).

In one embodiment R¹ represents hydrogen.

In one embodiment R¹ represents C₁₋₆alkyl. In one embodiment R¹represents methyl.

In one embodiment each R² is independently selected from hydroxyl,halogen, cyano, C₁₋₄alkyl, C₂₋₄alkenyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl, haloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl,R¹³, C₁₋₄alkoxy substituted with R¹³, —C(═O)—R¹³, C₁₋₄alkyl substitutedwith NR⁷R⁸, C₁₋₄alkoxy substituted with NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸;or when two R² groups are attached to adjacent carbon atoms they may betaken together to form a radical of formula —O—(C(R¹⁷)₂)_(p)—O— whereinR¹⁷ represents hydrogen or fluorine and p represents 1 or 2.

In one embodiment each R² is independently selected from hydroxyl,halogen, cyano, C₁₋₄alkyl, C₂₋₄alkenyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl,hydroxyC₁₋₄alkoxy, haloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, R¹³, C₁₋₄alkoxysubstituted with R¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with NR⁷R⁸,C₁₋₄alkoxy substituted with NR⁷R⁸, —NR⁷R⁸ or —C(═O)—NR⁷R⁸.

In one embodiment one or more R² represents C₁₋₄alkoxy, for exampleCH₃O—, or halo, for example fluoro or chloro, in particular fluoro.

In one embodiment one or more R² represents C₁₋₄alkoxy, for exampleCH₃O—.

In one embodiment n is equal to 0. In one embodiment n is equal to 1. Inone embodiment n is equal to 2. In one embodiment n is equal to 3. Inone embodiment n is equal to 4.

In one embodiment, n is equal to 2, 3 or 4.

In one embodiment n is equal to 2 and one R² is present at the3-position and the other is present at the 5-position.

In one embodiment n is equal to 2 and one R² is present at the3-position and the other is present at the 5-position and each R²represents C₁₋₄alkoxy, for example each R² represents CH₃O—.

In one embodiment n is equal to 3 and one R² is present at the2-position, one R² is present at the 3-position and one R² is present atthe 5-position.

In one embodiment n is equal to 3 and one R² is present at the3-position and represents C₁₋₄alkoxy, for example CH₃O—; one R² ispresent at the 5-position and represents C₁₋₄alkoxy, for example CH₃O—;one R² is present at the 2-position and represents halogen, for examplefluoro or chloro, in particular fluoro.

In one embodiment n is equal to 4 and one R² is present at the2-position, one R² is present at the 3-position, one R² is present atthe 5-position and one R² is present at the 6-position.

In one embodiment n is equal to 4 and one R² is present at the3-position and represents C₁₋₄alkoxy, for example CH₃O—; one R² ispresent at the 5-position and represents C₁₋₄alkoxy, for example CH₃O—;one R² is present at the 2-position and represents halogen, for examplefluoro, and one R² is present at the 6-position and represents halogen,for example fluoro.

In one embodiment, R³ represents C₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, hydroxyC₂₋₆alkynyl, haloC₁₋₆alkyl optionallysubstituted (e.g. substituted) with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups or with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkylsubstituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with oneor two halogens and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkylsubstituted with carboxyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with R⁹ and optionallysubstituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with hydroxyland R⁹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —C(═O)—R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, hydroxyC₁₋₆alkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl, R¹³, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)— or C₁₋₆alkyl substituted with—P(═O)(OC₁₋₆alkyl)₂.

In one embodiment R³ represents C₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkylsubstituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with oneor two halogens and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkylsubstituted with carboxyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with hydroxyl and R⁹,—C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with —C(═O)—R⁹, C₂₋₆alkynyl substituted with R⁹,hydroxyC₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, R¹³ or C₁₋₆alkylsubstituted with C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—.

In one embodiment R³ represents C₁₋₆alkyl, hydroxyC₁₋₆alkyl,haloC₁₋₆alkyl, haloC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, hydroxyC₂₋₆alkynyl, C₁₋₆alkylsubstituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groupsor with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹³R¹¹, C₁₋₆alkylsubstituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with oneor two halo atoms and —NR¹⁰R¹¹. C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted withcarboxyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹, C₁₋₆alkylsubstituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with R⁹ and substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substituted with hydroxyl and R⁹,—C₁₋₆alkyl-C(R¹²)═N—O—R¹², —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹,C₁₋₆alkyloxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally besubstituted with one or two hydroxyl groups, C₂₋₆alkenyl, C₂₋₆alkynyl,R¹³, or C₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂.

In one embodiment, R³ represents C₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkylsubstituted with hydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with oneor two halogens and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with hydroxyl and R⁹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹²,C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—R⁹, C₂₋₆alkynyl substituted with R⁹, hydroxyC₁₋₆alkoxy,C₂₋₆alkenyl, C₂₋₆alkynyl or R¹³.

In one embodiment R³ represents hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkyl substituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with R⁹, or C₂₋₆alkynyl.

In one embodiment R³ represents C₂₋₆alkynyl, haloC₁₋₆alkyl optionallysubstituted with —O—C(═O)—C₁₋₆alkyl, hydroxyC₁₋₆alkyl optionallysubstituted with —O—C(═O)—C₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups or with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, or C₁₋₆alkyl substituted with—O—C(═O)—NR¹⁰R¹¹.

In one embodiment R³ represents hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkyl substituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups or with —O—C₂₋₆alkynyl substituted withR⁹, or C₂₋₆alkynyl.

In one embodiment R³ represents hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkyl substituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁹R¹¹,C₂₋₆alkynyl substituted with R⁹, or C₂₋₆alkynyl.

In one embodiment R³ represents hydroxyC₁₋₆alkyl, C₁₋₆alkyl substitutedwith R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkoxyC₁₋₆alkyl, orC₂₋₆alkynyl.

In one embodiment R³ represents hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkyl substituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with R⁹, or C₂₋₆alkynyl.

In one embodiment R³ represents C₂₋₆alkynyl. R³ may represent—CH₂—C≡C—H.

In one embodiment R³ represents C₂₋₆alkynyl (e.g. —CH₂—C≡C—) substitutedwith R⁹. R⁹ may represent an optionally substituted aromatic 6-memberedmonocyclic heterocycle containing one or two nitrogen heteroatoms, forexample pyridinyl or pyrimidinyl. The heterocyclyl may be substituted,for example substituted with one C₁₋₄alkoxyl substituent, for example—OCH₃. R³ may represent —CH₂—C≡C-(2-pyridinyl), or—CH₂—C≡C-(2-pyrimidinyl). Or R⁹ may represent an optionally substitutedaromatic 5-membered monocyclic heterocycle containing one or twonitrogen heteroatoms, for example imidazolyl. The heterocycle may besubstituted, for example substituted with C₁₋₄alkyl, for example methyl.R³ may represent —CH₂—C≡C— (imidazol-2-yl substituted with methyl inposition 1).

In one embodiment when R³ represents C₁₋₆alkyl (e.g. C₁₋₄alkyl)substituted with R⁹. R⁹ represents an optionally substituted saturatedor an aromatic 5 or 6 membered monocyclic heterocyclyl, for exampleoptionally substituted isoxazolidinyl, pyrimidinyl, imidazolyl orpyrrolidinyl.

In one embodiment when R³ represents C₁₋₆alkyl (e.g. C₁₋₄alkyl)substituted with R⁹, wherein R⁹ represents an optionally substitutedaromatic 6 membered monocyclic heterocyclyl containing one or twonitrogen heteroatom, for example pyrimidinyl or pyridinyl.

In one embodiment when R³ represents C₁₋₆alkyl (e.g. methyl or n-propyl)substituted with R⁹, wherein R⁹ represents unsubstituted isoxazolidinyl,unsubstituted pyrimidinyl, unsubstituted imidazolyl (e.g.imidazol-2-yl), imidazolyl (e.g. imidazol-2-yl) substituted with—S(O)₂—N(CH₃)₂, oxo-substituted pyrrolidinyl or pyrrolidinyl substitutedby 3-methoxy-pyrimidin-2-yl.

In one embodiment R³ represents C₁₋₆alkyl substituted with hydroxyl,halo and/or —NR¹⁰R¹¹. In one embodiment R³ represents C₁₋₆alkylsubstituted with hydroxyl, halo or —NR¹⁰R¹¹, wherein the C₁₋₆alkyl groupis a straight chain alkyl group e.g. 2-ethyl, n-propyl, n-butyl. In afurther embodiment R³ represents C₁₋₆alkyl substituted with hydroxyl or—NR¹⁰R¹¹.

In one embodiment R³ represents hydroxyC₁₋₆alkyl. R³ may represent—CH₂CH₂OH or —CH₂CH₂CH₂OH.

In one embodiment R³ represents hydroxyhaloC₁₋₆alkyl, for example R³ mayrepresent —CH₂CHOHCF₃.

In one embodiment R³ represents C₁₋₆alkyl substituted with —NR¹⁰R¹¹.

In one embodiment R³ represents C₁₋₄alkyl substituted with —NR¹⁰R¹¹. Inone embodiment R³ represents C₁₋₄alkyl substituted —NR¹⁰R¹¹, wherein theC₁₋₄alkyl group is a straight chain alkyl group e.g. 2-ethyl, n-propyl.In one embodiment R³ represents C₁₋₄alkyl substituted with —NR¹⁰R¹¹,wherein the C₁₋₄alkyl group is an ethylene group (—CH₂CH₂—).

In one embodiment when R³ represents C₁₋₆alkyl (e.g. 2-ethyl, n-propyl)substituted with —NR¹⁰R¹¹, wherein R¹⁹ and R¹¹ are independentlyselected from hydrogen, C₁₋₄alkyl and haloC₁₋₆alkyl (e.g. hydrogen,iso-propyl or —CH₂CF₃).

In one embodiment when R³ represents C₁₋₆alkyl substituted with—NR¹⁰R¹¹, R¹⁹ and R¹¹ have the following meanings:

a) each of R¹⁹ and R¹¹ represent hydrogen. R³ may representCH₂CH₂CH₂NH₂;

b) one of R¹⁰ and R¹¹ represents hydrogen and the other representsC₁₋₆alkyl, for example CH(CH₃)₂. R³ may represent —CH₂CH₂NHCH(CH₃)₂; or

c) one of R¹⁰ and R¹¹ represents hydrogen and the other representshaloC₁₋₆alkyl, for example CH₂CF₃. R³ may represent —CH₂CH₂CH₂NHCH₂CF₃;

In one embodiment R³ represents —CH₂CH₂NHCH(CH₃)₂.

R^(3a) may represent NR¹⁰R¹¹, hydroxyl, C₁₋₆alkyl, hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkylsubstituted with hydroxyl and —NR¹⁹R¹¹, C₁₋₆alkyl substituted with oneor two halogens and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with carboxyl, C₁₋₆alkyl substituted with—O—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substitutedwith hydroxyl and R⁹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substitutedwith —C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —C(═O)—R⁹, C₂₋₆alkynylsubstituted with R⁹, hydroxyC₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl, R¹³ orC₁₋₆alkyl substituted with C₁₋₆alkoxyC₁₋₆alkyl-C(═O)—.

In one embodiment R^(3a) is —NR¹⁰R¹¹, hydroxyl, hydroxyC₁₋₆alkyl,cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹,C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted with hydroxyland —NR¹⁰R¹¹, or C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹.

In one embodiment R^(3a) represents hydroxyl, C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—O—C₁₋₆alkyl.

In one embodiment R^(3a) represents C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹. In one embodiment R^(3a) represents C₁₋₄alkylsubstituted —C(═O)—NR¹⁰R¹¹, wherein the C₁₋₄alkyl group is a straightchain alkyl group e.g. methyl. In one embodiment, R^(3a) representsC₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, wherein R¹⁰ and R¹¹ representhydrogen.

In one embodiment, R^(3a) represents cyanoC₁₋₆alkyl, for example R^(3a)represents —CH₂—CN.

In one embodiment, R^(3a) represents C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl, for example R^(3a) represents —CH₂—COOCH₃ or—CH₂—COOCH₂CH₃.

In one embodiment, R^(3a) represents hydroxyC₁₋₆alkyl, for exampleCH₂—CH₂—OH.

In one embodiment R^(3a) represents hydroxyl.

In one embodiment R^(3b) represents hydrogen.

In one embodiment R^(3b) represents hydroxyl.

In one embodiment R^(3a) represents hydroxyl and R^(3b) representshydrogen.

In one embodiment R^(3a) represents hydroxyl, C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, or C₁₋₆alkylsubstituted with —C(═O)—O—C₁₋₆alkyl and R^(3b) represents hydrogen.

In one embodiment R^(3a) and R^(3b) are taken together to form ═O, toform ═NR¹⁰, to form cyclopropyl together with the carbon atom to whichthey are attached, to form ═CH—C₀₋₄alkyl substituted with R^(3c), or toform

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining one heteroatom selected from N, O or S, said heteroatom notbeing positioned in alpha position of the double bond, wherein ring A isoptionally being substituted with cyano, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,H₂N—C₁₋₄alkyl, (C₁₋₄alkyl)NH—C₁₋₄alkyl, (C₁₋₄alkyl)₂N—C₁₋₄alkyl,(haloC₁₋₄alkyl)NH—C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, —C(═O)—NH₂,—C(═O)—NH(C₁₋₄alkyl), —C(═O)—N(C₁₋₄alkyl)₂.

In one embodiment R^(3a) and R^(3b) are taken together to form ═O, toform cyclopropyl together with the carbon atom to which they areattached, to form ═CH—C₀₋₄alkyl substituted with R^(3c), or to form

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining one heteroatom selected from N, O or S, said heteroatom notbeing positioned in alpha position of the double bond.

In one embodiment R^(3a) and R^(3b) are taken together to form ═O.

In one embodiment R^(3a) and R^(3b) are taken together to formcyclopropyl together with the carbon atom to which they are attached.

In one embodiment R^(3a) and R^(3b) are taken together to form═CH—C₀₋₄alkyl substituted with R^(3c).

In one embodiment R^(3c) represents hydrogen.

In one embodiment R^(3c) represents cyano.

In one embodiment R^(3c) represents hydroxyl, C₁₋₆alkoxy, R⁹, —NR¹⁰R¹¹,cyano, —C(═O)—C₁₋₆alkyl or —CH(OH)—C₁₋₆alkyl.

In one embodiment R^(3c) represents hydroxyl, —NR¹⁰R¹¹, cyano, or—C(═O)—C₁₋₆alkyl.

In one embodiment R^(3a) and R^(3b) are taken together to form═CH—C₀₋₄alkyl in the Z configuration.

In one embodiment R^(3a) and R^(3b) are taken together to form═CH-cyano. In one embodiment, R^(3a) and R^(3b) are taken together toform ═CH-cyano in the Z configuration.

In one embodiment R^(3a) and R^(3b) are taken together to form═CH-cyano. In one embodiment, R^(3a) and R^(3b) are taken together toform ═CH-cyano in the E configuration.

In one embodiment, R⁹ is selected from:

an optionally substituted C₃₋₈cycloalkyl,

an optionally substituted aromatic 5 membered monocyclic heterocyclyl,

an optionally substituted saturated 6 membered monocyclic heterocyclyl,

a saturated or an aromatic 3, 4, 5 or 6 membered monocyclic heterocyclylcontaining one or two oxygen heteroatoms,

an optionally substituted 4 membered heterocyclyl containing one oxygenheteroatom,

an optionally substituted aromatic 6 membered monocyclic heterocyclecontaining one or two nitrogen heteroatoms,

a partially saturated 6 membered monocyclic heterocyclyl containing onenitrogen heteroatom which may optionally be substituted,

an optionally substituted saturated 4 membered monocyclic heterocyclylcontaining one nitrogen heteroatom,

a saturated 5 membered monocyclic heterocyclyl containing one nitrogenheteroatom,

a saturated 6 membered monocyclic heterocyclyl containing one nitrogenheteroatom,

a bicyclic heterocyclyl containing a benzene ring fused to a 5- or6-membered ring containing 1, 2 or 3 ring heteroatoms,

a 4, 5 or 6 membered monocyclic saturated heterocycle substituted withtwo substituents which are attached to the same atom and which are takentogether to form a 4 to 7-membered saturated monocyclic heterocyclylcontaining at least one heteroatom selected from N, O or S,an optionally substituted aromatic 5 membered monocyclic heterocyclylcontaining one sulphur heteroatom,an optionally substituted aromatic 5 membered monocyclic heterocyclylcontaining one sulphur and one nitrogen heteroatom,a saturated 6 membered monocyclic heterocyclyl containing two nitrogenheteroatoms,an aromatic 5 membered monocyclic heterocyclyl containing four nitrogenheteroatoms,an aromatic 5 membered monocyclic heterocyclyl containing one oxygen andtwo nitrogen heteroatoms,an optionally substituted aromatic 5 membered monocyclic heterocyclylcontaining two nitrogen heteroatoms,an optionally substituted aromatic 5 membered monocyclic heterocyclylcontaining three nitrogen heteroatoms,a saturated 5 membered monocyclic heterocyclyl containing one nitrogenand one oxygen heteroatom,a saturated 6 membered monocyclic heterocyclyl containing one nitrogenand one sulphur heteroatom,a saturated 7 membered monocyclic heterocyclyl containing two nitrogenheteroatoms,a saturated 7 membered monocyclic heterocyclyl containing one nitrogenand one oxygen heteroatom, andphenyl or naphthyl, in particular phenyl.

In one embodiment, R⁹ represents an optionally substituted 5 memberedaromatic or saturated heterocycle, such as for example imidazolyl,pyrolidinyl, isoxazolidinyl. Optional substituents may represent ═O, a 5or 6-membered aromatic monocyclic heterocyclyl containing at least oneheteroatom selected from N, O or S wherein said heterocyclyl isoptionally substituted with R¹⁶; or —S(═O)₂—NR¹⁴R¹⁵.

In one embodiment, R⁹ represents an optionally substituted 5 memberedaromatic or saturated heterocycle, such as for example imidazolyl,pyrolidinyl, isoxazolidinyl. Optional substituents may represent ═O, a 5or 6-membered aromatic monocyclic heterocyclyl containing at least oneheteroatom selected from N, O or S wherein said heterocyclyl isoptionally substituted with R¹⁶; —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl, orC₁₋₄alkyl substituted with —NH—S(═O)₂-haloC₁₋₄alkyl.

In one embodiment, R⁹ represents C₃₋₆cycloalkyl, such as for examplecyclopropyl, a 3 membered saturated heterocyclyl, such as for exampleoxiranyl, an optionally substituted 5 membered saturated heterocycle,such as for example pyrrolidinonyl, an optionally substituted 6 memberedaromatic or saturated heterocycle, such as for example pyridyl,pyrimidinyl, pyrazinyl, piperazinyl, or morpholinyl, an optionallysubstituted bicyclic heterocycle, such as for example1H-isoindol-1,3-dione. Optional substituents may represent ═O,C₁₋₄alkoxy, C1-4alkyl substituted with NR¹⁴R¹⁵, hydroxyC₁₋₄alkyl, orC₁₋₄alkyl-C(═O)—.

In one embodiment, R⁹ represents an optionally substituted 5 memberedaromatic heterocycle, such as for example imidazolyl, or an optionallysubstituted 6 membered aromatic heterocycle, such as for examplepyridyl, pyrimidinyl or pyrazinyl. Optional substituents may representC₁₋₄alkoxy or —S(═O)₂—NR¹⁴R¹⁵.

In one embodiment, R⁹ represents an optionally substituted 5 memberedaromatic heterocycle, such as for example imidazolyl. Optionalsubstituents may represent —S(═O)₂—NR¹⁴R¹⁵.

In one embodiment, R⁹ represents an optionally substituted 6 memberedaromatic heterocycle, such as for example pyridinyl or pyrimidinyl.Optional substituents may represent C₁₋₄alkoxy.

In one embodiment R¹⁰ represents hydrogen or C₁₋₆alkyl or haloC₁₋₆alkyl.

In one embodiment R¹⁰ is hydrogen.

In one embodiment R¹¹ represents hydrogen, C₁₋₆alkyl, haloC₁₋₆alkyl,—C(═O)—C₁₋₆alkyl, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, hydroxyC₁₋₆alkyl,—C(═O)-hydroxyhaloC₁₋₆alkyl, —C(═O)—R⁶, cyanoC₁₋₆alkyl, R⁶, —C(═O)—R⁶,C₁₋₆alkyl substituted with R⁶, —C(═O)-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with —Si(CH₃)₃, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₆alkoxy,hydroxyhaloC₁₋₆alkyl, carboxyl, or C₁₋₆alkoxyC₁₋₆alkyl.

In one embodiment R¹⁰ and R¹¹ represent hydrogen or C₁₋₆alkyl.

In one embodiment, R⁶ represents a 6-membered monocyclic saturatedheterocyclyl which is optionally substituted. For example piperazinyl ormorpholinyl or tetrahydropyranyl, optionally substituted with halogen,C₁₋₆alkyl, or C₁₋₆alkyl-O—C(═O)—.

In one embodiment, R⁶ represents a 6-membered monocyclic aromaticheterocyclyl which is optionally substituted. For example pyridinyl,optionally substituted with halogen, C₁₋₆alkyl, or C₁₋₆alkyl-O—C(═O)—.

In one embodiment R⁶ represents an optionally substituted saturated 4 to7-membered monocyclic heterocyclyl containing at least one heteroatomselected from N, O or S, such as for example tetrahydropyran.

In one embodiment, R¹² represents hydrogen or C₁₋₄alkyl optionallysubstituted with C₁₋₄alkyloxy.

In one embodiment, R¹³ represents a saturated 4 to 6-membered monocyclicheterocyclyl containing at least one heteroatom selected from N or O.

In one embodiment, R¹⁴ and R¹⁵ each independently represent hydrogen orC₁₋₄alkyl. In one embodiment, R¹⁴ and R¹⁵ each independently representC₁₋₄alkyl.

In one embodiment, R²² and R²³ each independently represent hydrogen.

In one embodiment, W is —N(R³)— and Y is D (E is a bond).

In one embodiment, W is —N(R³)— and Y is -E-D wherein E is other than abond.

In one embodiment, W is —N(R³)—, and Y is —CR¹⁸═N—OR¹⁹.

In one embodiment, W is —N(R³)—, Y is -E-D, wherein E is a bond and D isa 5 or 6 membered monocyclic aromatic heterocyclyl, wherein saidheterocyclyl may optionally be substituted by one or more (e.g. 1, 2 or3) R¹ groups, in particular D is pyrazolyl optionally substituted withC₁₋₆alkyl, more in particular D is pyrazolyl optionally substituted withC₁₋₆alkyl and n is 2, even more in particular D is pyrazolyl optionallysubstituted with C₁₋₆alkyl; n is 2, R² is C₁₋₆alkyloxy, even further inparticular D is pyrazolyl optionally substituted with C₁₋₆alkyl; n is 2,R² is C₁₋₆alkyloxy and said R² is placed in position 3 and 5.

In one embodiment, W is —N(R³)—, Y is -E-D, wherein E is a bond and D ispiperidinyl, pyridinyl, phenyl, pyrrolyl, imidazolyl, triazolyl,pyrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl, cyclopentyl,azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl,1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrrolyl, pyrimidinyl,pyrrolidinyl, thiadiazolyl, oxadiazolyl, said rings being optionallysubstituted, more in particular D is piperidinyl, pyridinyl, phenyl,pyrrolyl, imidazolyl, triazolyl, pyrolopyridinyl, 1,3-benzodioxolyl,indolyl, thiazolyl, cyclopentyl, azetidinyl, morpholinyl, tetrazolyl,oxazolyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrrolyl,pyrimidinyl, pyrrolidinyl, thiadiazolyl, oxadiazolyl, said rings beingoptionally substituted and n is 2, even more in particular D ispiperidinyl, pyridinyl, phenyl, pyrrolyl, imidazolyl, triazolyl,pyrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl, cyclopentyl,azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl,1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrrolyl, pyrimidinyl,pyrrolidinyl, thiadiazolyl, oxadiazolyl, said rings being optionallysubstituted; n is 2, R² is C₁₋₆alkyloxy, even further in particular D ispiperidinyl, pyridinyl, phenyl, pyrrolyl, imidazolyl, triazolyl,pyrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl, cyclopentyl,azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl,1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrrolyl, pyrimidinyl,pyrrolidinyl, thiadiazolyl, oxadiazolyl, said rings being optionallysubstituted; n is 2, R² is C₁₋₆alkyloxy and said R² is placed inposition 3 and 5.

In one embodiment, W is —C(R^(3a)R^(3b))— and Y is D (E is a bond).

In one embodiment, W is —C(R^(3a)R^(3b))— and Y is -E-D wherein E isother than a bond.

In one embodiment, W is —C(R^(3a)R^(3b))—, and Y is —CR¹⁸═N—OR¹⁹.

In one embodiment, W is —C(R^(3a)R^(3b))—, Y is -E-D, wherein E is abond and D is a 5 or 6 membered monocyclic aromatic heterocyclyl,wherein said heterocyclyl may optionally be substituted by one or more(e.g. 1, 2 or 3) R¹ groups, in particular D is pyrazolyl optionallysubstituted with C₁₋₆alkyl, more in particular D is pyrazolyl optionallysubstituted with C₁₋₆alkyl and n is 2, even more in particular D ispyrazolyl optionally substituted with C₁₋₆alkyl; n is 2, R² isC₁₋₆alkyloxy, even further in particular D is pyrazolyl optionallysubstituted with C₁₋₆alkyl; n is 2, R² is C₁₋₆alkyloxy and said R² isplaced in position 3 and 5.

In one embodiment, W is —C(R^(3a)R^(3b))—, Y is -E-D, wherein E is abond and D is piperidinyl, pyridinyl, phenyl, pyrrolyl, imidazolyl,triazolyl, pyrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl,cyclopentyl, azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl,1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrrolyl, pyrimidinyl,pyrrolidinyl, thiadiazolyl, oxadiazolyl, said rings being optionallysubstituted, more in particular D is piperidinyl, pyridinyl, phenyl,pyrrolyl, imidazolyl, triazolyl, pyrolopyridinyl, 1,3-benzodioxolyl,indolyl, thiazolyl, cyclopentyl, azetidinyl, morpholinyl, tetrazolyl,oxazolyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrrolyl,pyrimidinyl, pyrrolidinyl, thiadiazolyl, oxadiazolyl, said rings beingoptionally substituted and n is 2, even more in particular D ispiperidinyl, pyridinyl, phenyl, pyrrolyl, imidazolyl, triazolyl,pyrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl, cyclopentyl,azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl,1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrrolyl, pyrimidinyl,pyrrolidinyl, thiadiazolyl, oxadiazolyl, said rings being optionallysubstituted; n is 2, R² is C₁₋₆alkyloxy, even further in particular D ispiperidinyl, pyridinyl, phenyl, pyrrolyl, imidazolyl, triazolyl,pyrolopyridinyl, 1,3-benzodioxolyl, indolyl, thiazolyl, cyclopentyl,azetidinyl, morpholinyl, tetrazolyl, oxazolyl, piperazinyl,1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrrolyl, pyrimidinyl,pyrrolidinyl, thiadiazolyl, oxadiazolyl, said rings being optionallysubstituted; n is 2, R² is C₁₋₆alkyloxy and said R² is placed inposition 3 and 5.

In one embodiment, n represents an integer equal to 2, 3 or 4; R²represents C₁₋₄alkoxy or halogen, for example CH₃O— or fluoro; R³represents hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substitutedwith R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₂₋₆alkynyl substitutedwith R⁹ or C₂₋₆alkynyl; Y is -E-D wherein E represents a bond, Drepresents pyrazolyl, in particular pyrazol-4-yl, optionally substitutedwith C₁₋₆alkyl. hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl or R⁶; W is —N(R³)— or —C(R^(3a)R^(3b))— whereinR^(3a) is hydroxyl, R^(3b) is hydrogen.

In one embodiment, n represents an integer equal to 2, 3 or 4; R²represents C₁₋₄alkoxy or halogen, for example CH₃O— or fluoro or chloro;R³ represents hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₂₋₆alkynylsubstituted with R⁹ or C₂₋₆alkynyl; R^(3a) represents hydroxyl,C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, cyanoC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl; R^(3b)represents hydrogen; or R^(3a) and R^(3b) are taken together to form ═Oor to form ═CH—C₀₋₄alkyl substituted with R^(3c); Y is -E-D wherein Erepresents a bond, D represents an optionally substituted 5 memberedheterocycle, an optionally substituted 6 membered heterocycle or phenyl,in particular an optionally substituted aromatic 5 membered heterocycle,an optionally substituted saturated, partially saturated or aromatic 6membered heterocycle or phenyl, in particular pyrazol-4-yl, optionallysubstituted with C₁₋₆alkyl. hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl or R⁶, or phenyl, or pyridyl or morpholinyl or1,2,3,6-tetrahydropyridyl or pyrrolyl optionally substituted withC₁₋₆alkyl.

In one embodiment, n represents an integer equal to 2, 3 or 4; R²represents C₁₋₄alkoxy or halogen, for example CH₃O— or fluoro or chloro;R³ represents hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₂₋₆alkynylsubstituted with R⁹ or C₂₋₆alkynyl; R^(3a) represents hydroxyl,C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹, cyanoC₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl; R^(3b)represents hydrogen; or R^(3a) and R^(3b) are taken together to form ═Oor to form ═CH—C₀₋₄alkyl substituted with R^(3c); R^(3c) representscyano; Y is -E-D wherein E represents a bond, D represents an optionallysubstituted 5 membered heterocycle, an optionally substituted 6 memberedheterocycle or phenyl, in particular an optionally substituted aromatic5 membered heterocycle, an optionally substituted saturated, partiallysaturated or aromatic 6 membered heterocycle or phenyl, in particularpyrazol-4-yl, optionally substituted with C₁₋₆alkyl. hydroxyC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl or R⁶, or phenyl, orpyridyl or morpholinyl or 1,2,3,6-tetrahydropyridyl or pyrrolyloptionally substituted with C₁₋₆alkyl; W is —N(R³)— or—C(R^(3a)R^(3b))—; R⁹ represents an optionally substituted 5 memberedaromatic or saturated heterocycle, such as for example imidazolyl,pyrolidinyl, isoxazolidinyl, said heterocycles being optionallysubstituted with ═O, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl, C₁₋₄alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₄alkyl, or a 5 or 6-membered aromatic monocyclicheterocyclyl containing at least one heteroatom selected from N, O or Swherein said heterocyclyl, for example pyrimidinyl, is optionallysubstituted with R¹⁶; or R⁹ represents an optionally substituted 6membered aromatic heterocycle, such as for example pyridinyl orpyrimidinyl, said heterocycles being optionally substituted withC₁₋₄alkoxy; R¹⁶ represents C₁₋₄alkoxy; R¹⁰ and R¹¹ each independentlyrepresent hydrogen or C₁₋₆alkyl; R¹⁴ and R¹⁵ each independentlyrepresent hydrogen or C₁₋₄alkyl.

In one embodiment there is provided compounds of formula (I) includingany tautomeric or stereochemically isomeric form thereof, wherein

W is —N(R³)— or —C(R^(3a)R^(3b))—;

each R² is independently selected from halogen, for example fluoro orchloro, or C₁₋₄alkoxy, for example —OCH₃;

Y represents -E-D;

E represents a bond;

D represents a 3 to 12 ring membered monocyclic or bicyclic carbocyclylor a 3 to 12 ring membered monocyclic or bicyclic heterocyclylcontaining at least one heteroatom selected from N, O or S, for examplepyrazolyl, phenyl, pyridyl, morpholinyl, 1,2,3,6-tetrahydropyridyl,pyrrolyl, piperidinyl, wherein said carbocyclyl and heterocyclyl mayeach be optionally substituted by one or more (e.g. 1, 2 or 3) R¹groups;R¹ represents hydrogen, C₁₋₆alkyl, for example —CH₃, hydroxyC₁₋₆alkyl,for example —CH₂CH₂OH, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, forexample —CH₂CH₂—S(═O)₂—CH₃, R⁶; for example tetrahydropyran-2-yl, orC(═O)—O—C₁₋₆alkyl;R^(3a) represents hydroxyl; or R^(3a) represents hydroxyl, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁹R¹¹, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl,C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl;R^(3b) represents hydrogen; orR^(3a) and R^(3b) are taken together to form ═O or to form ═CH—C₀₋₄alkylsubstituted with cyano,R³ represents

-   -   hydroxyC₁₋₆alkyl, for example —CH₂CH₂OH, —CH₂CH₂CH₂OH,    -   hydroxyhaloC₁₋₆alkyl, for example —CH₂CHOH—CF₃,    -   C₁₋₆alkyl substituted with R⁹, for example        -   methyl substituted with pyriminidin-2-yl,        -   methyl substituted with imidazol-2-yl optionally substituted            with —S(═O)₂—N(CH₃)₂ for example in the 3 position,        -   propyl substituted with pyrrolidin-1-yl substituted in the 2            position by ═O or —CH₂—NH—SO₂—CF₃,        -   propyl substituted with isoxazolin-2-yl,        -   pyrrolidin-4-yl substituted in the 1 position by            pyrimidin-2-yl substituted in the 4 position by OCH₃,        -   methyl substituted with pyrrolidin-5-yl substituted in the 2            position by ═O,    -   C₁₋₆alkyl substituted with —NR¹⁰R¹¹, for example        —CH₂CH₂NHCH(CH₃)₂, —CH₂CH₂CH₂NHCH₂CF₃, —CH₂CH₂NHCH₃,    -   C₂₋₆alkynyl substituted with R⁹, for example        -   —CH₂—C(triple bond)C— substituted with pyridin-2-yl            substituted in the 3 position with —OCH₃        -   —CH₂—C(triple bond)C— substituted with imidazol-2-yl            substituted in the 1 position with —CH₃        -   —CH₂—C(triple bond)C— substituted with pyrimidin-2-yl            substituted in the 4 position with OCH₃, or    -   C₂₋₆alkynyl; for example —CH₂—C≡C—H; and        n independently represents an integer equal to 2, 3 or 4;        the N-oxides thereof, the pharmaceutically acceptable salts        thereof or the solvates thereof.

In one embodiment the compound of formula (I) is a compound of formula(Ia) including any tautomeric or stereochemically isomeric form thereof:

wherein n, R¹, R² and R³ are as defined herein;the N-oxides thereof, the pharmaceutically acceptable salts thereof orthe solvates thereof.

A compound of formula (Ia) including any tautomeric or stereochemicallyisomeric form thereof wherein:

R¹ represents hydrogen, C₁₋₆alkyl (e.g methyl), —C(═O)—O—C₁₋₆alkyl (e.g.—C(═O)—O—C(CH₃)₃), hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl or optionally substituted non-aromatic 4 to 7-membered(e.g. 6 membered) monocyclic heterocyclyl containing at least oneheteroatom selected from N, O or S (e.g. tetrahydropyranyl);R² represents C₁₋₄alkoxy, for example CH₃O—, or halo, for example fluoroor chloro;n=2; or n=2, 3 or 4; andR³ represents hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₂₋₆alkynylsubstituted with R⁹, or C₂₋₆alkynyl; the N-oxides thereof, thepharmaceutically acceptable salts thereof or the solvates thereof.

A compound of formula (Ia) including any tautomeric or stereochemicallyisomeric form thereof wherein

R¹ represents hydrogen, C₁₋₆alkyl (e.g methyl), hydroxyC₁₋₆alkyl (e.g.—CH₂CH₂OH), C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl (e.g.—CH₂CH₂—SO₂—CH₃) or optionally substituted non-aromatic 4 to 7-membered(e.g. 6 membered) monocyclic heterocyclyl containing at least oneheteroatom selected from N, O or S (e.g. tetrahydropyran);R² represents C₁₋₄alkoxy, for example CH₃O—, or halo, for example fluoroor chloro;n=2; or n=2, 3 or 4; andR³ represents(i) hydroxyC₁₋₆alkyl, R³ may represent —CH₂CH₂OH or —CH₂CH₂CH₂OH;(ii) hydroxyhaloC₁₋₆alkyl, for example —CH₂CHOHCF₃;(iii) C₁₋₆alkyl (e.g. 2-ethyl, n-propyl) substituted with —NR¹⁰R¹¹,wherein R¹⁰ and R¹¹ are independently selected from hydrogen, C₁₋₆alkyland haloC₁₋₆alkyl (e.g. hydrogen, iso-propyl or —CH₂CF₃);(iv) C₁₋₆alkyl (e.g. methyl or n-propyl) substituted with R⁹, wherein R⁹represents optionally substituted saturated or an aromatic 5 or 6membered monocyclic heterocyclyl (e.g. unsubstituted isoxazolidinyl,unsubstituted pyrimidinyl, unsubstituted imidazolyl, imidazolylsubstituted with —S(O)₂—N(CH₃)₂, oxo-substituted pyrrolidinyl,pyrrolidinyl substituted by 3-methoxy-pyrimidin-2-yl), or pyrrolidinylsubstituted with —CH₂—NH—SO₂—CF₃;(v) C₂₋₆alkynyl (e.g. —CH₂—C≡C—H); or(vi) C₂₋₆alkynyl (e.g. —CH₂—C≡C—) substituted with R⁹, wherein R⁹ mayrepresent an optionally substituted aromatic 5 or 6-membered monocyclicheterocycle containing one or two nitrogen heteroatoms, for examplepyridinyl or pyrimidinyl or imidazolyl (e.g. —CH₂—C≡C-(2-pyridinyl), or—CH₂—C≡C-(2-pyrimidinyl)) substituted, for example substituted with oneC₁₋₄alkoxyl substituent, for example —OCH₃, or —CH₂—C≡C-(2-imidazolyl)which may be substituted for example with methyl,the N-oxides thereof, the pharmaceutically acceptable salts thereof orthe solvates thereof.

A compound of formula (Ia) including any tautomeric or stereochemicallyisomeric form thereof wherein

R¹ represents hydrogen, C₁₋₆alkyl (e.g methyl), hydroxyC₁₋₆alkyl (e.g.—CH₂CH₂OH), C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl (e.g.—CH₂CH₂—SO₂—CH₃) or optionally substituted non-aromatic 4 to 7-membered(e.g. 6 membered) monocyclic heterocyclyl containing at least oneheteroatom selected from N, O or S (e.g. tetrahydropyran);R² represents C₁₋₄alkoxy, for example CH₃O—, or halo, for example fluoroor chloro;n=2; or n=2, 3 or 4; andR³ represents(i) hydroxyC₁₋₆alkyl, R³ may represent —CH₂CH₂OH or —CH₂CH₂CH₂OH;(ii) hydroxyhaloC₁₋₆alkyl, for example —CH₂CHOHCF₃;(iii) C₁₋₆alkyl (e.g. 2-ethyl, n-propyl) substituted with —NR¹⁰R¹¹,wherein R¹⁹ and R¹¹ are independently selected from hydrogen, C₁₋₆alkyland haloC₁₋₆alkyl (e.g. hydrogen, iso-propyl or —CH₂CF₃);(iv) C₁₋₆alkyl (e.g. methyl or n-propyl) substituted with R⁹, wherein R⁹represents optionally substituted saturated or an aromatic 5 or 6membered monocyclic heterocyclyl (e.g. unsubstituted isoxazolidinyl,unsubstituted pyrimidinyl, unsubstituted imidazolyl, imidazolylsubstituted with —S(O)₂—N(CH₃)₂, oxo-substituted pyrrolidinyl,pyrrolidinyl substituted by 3-methoxy-pyrimidin-2-yl), or pyrrolidinylsubstituted with —CH₂—NH—SO₂—CF₃;(v) C₂₋₆alkynyl (e.g. —CH₂—C≡C—H); or(vi) C₂₋₆alkynyl (e.g. —CH₂—C≡C—) substituted with R⁹, wherein R⁹ mayrepresent an optionally substituted aromatic 5 or 6-membered monocyclicheterocycle containing one or two nitrogen heteroatoms, for examplepyridinyl or pyrimidinyl or imidazolyl (e.g. —CH₂—C≡C-(2-pyridinyl), or—CH₂—C≡C-(2-pyrimidinyl)) substituted, for example substituted with oneC₁₋₄alkoxyl substituent, for example —OCH₃, or —CH₂—C≡C-(2-imidazolyl)which may be substituted for example with methyl,the N-oxides thereof, the pharmaceutically acceptable salts thereof orthe solvates thereof.

In one embodiment the compound of formula (I) is a compound of formula(Ib) including any tautomeric or stereochemically isomeric form thereof:

wherein n, R¹, R², R^(3a) and R^(3b) are as defined herein;the N-oxides thereof, the pharmaceutically acceptable salts thereof orthe solvates thereof.

A compound of formula (Ib) including any tautomeric or stereochemicallyisomeric form thereof wherein:

R¹ represents C₁₋₆alkyl (e.g methyl);

R² represents C₁₋₄alkoxy, for example CH₃O—, or halo, for example fluoroor chloro;

n=2, 3 or 4; and

R^(3a) represents hydroxyl, C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹,cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with—C(═O)—O—C₁₋₆alkyl; R^(3b) represents hydrogen;

or R^(3a) and R^(3b) are taken together to form ═O or to form═CH—C₀₋₄alkyl substituted with R^(3c);

R^(3c) represents cyano;

the N-oxides thereof, the pharmaceutically acceptable salts thereof orthe solvates thereof.

In one embodiment, the compound of formula (I) is any one of thefollowing compounds

a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.

In one embodiment, the compound of formula (I) is any one of thefollowing compounds

a N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.

For the avoidance of doubt, it is to be understood that each general andspecific preference, embodiment and example for one substituent may becombined, whenever possible, with each general and specific preference,embodiment and example for one or more, preferably, all othersubstituents as defined herein and that all such embodiments areembraced by this application.

Methods for the Preparation of Compounds of Formula (I)

In this section, as in all other sections of this application unless thecontext indicates otherwise, references to formula (I) also include allother sub-groups and examples thereof as defined herein.

In general, compounds of formula (I) wherein W is —N(R³)— and Y is D (Eis a bond), said compounds being represented by formula (Ia), can beprepared according to the following reaction Scheme 1.

In scheme 1, a 6-nitro quinoline is halogenated, preferably brominated,on carbon C-3. The resulting intermediate wherein W₁ represent asuitable leaving group, such as for example halo, e.g. bromo and thelike, is then reacted with an intermediate of formula (III) to preparean intermediate of formula (II) in the presence of a suitable catalyst,such as for example tetrakis(triphenylphosphine)palladium (0) orpalladium (II) acetate or Pd(Ph₃)₂Cl₂ or PdCl₂ (dppf), a suitable base,such as for example sodium carbonate or cesium carbonate, a suitableligand, such as for example triphenylphosphine or xantphos, and asuitable solvent or solvent mixture, such as for example ethylene glycoldimethylether and water or dioxane and water. An intermediate of formula(II) can also be prepared by reacting the halogenated nitroquinolinewith D in the presence of a suitable catalyst, such as for examplePd₂dba₃, a suitable ligand, such as for example xantphos, a suitablebase, such as for example cesium carbonate, and a suitable solvent, suchas for example dioxane. An intermediate of formula (II) is then reducedinto a 6-aminoquinoline derivative by art-known methods (hydrogenationin the presence of a suitable catalyst, such as for example Raney Nickelor Pd on carbon, and a suitable solvent, such as for example an alcohol,e.g. methanol, or tetrahydrofuran, or mixtures thereof). This type ofreaction can also be performed in the presence of ammonium chloride,iron, and a suitable solvent, such as for example a mixture oftetrahydrofuran, water and methanol. Such derivative can then beconverted into an intermediate of formula (IV) wherein W₂ represent asuitable leaving group such as for example halo, e.g. bromo or iodo, byart-known diazotation methods. The 6-aminoquinoline derivative can alsoreact with a halophenyl derivative, such as a bromo or iodo phenylderivative, in the presence of a suitable catalyst, such as for exampletris(dibenzylideneacetone) dipalladium(0), a suitable base, such asCs₂CO₃, a suitable ligand, such as for example2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl or xantphosin a suitable solvent or solvent mixture, such as for example2-methyl-2-propanol to result in an intermediate of formula (VI).

The intermediate of formula (IV) can react with an intermediate offormula (V) in the presence of a suitable catalyst, such as for examplepalladium (II) acetate, a suitable base, such as sodium tert-butoxide orCs₂CO₃, a suitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], and asuitable solvent or solvent mixture, such as for example dioxane orethylene glycol dimethylether and water, resulting in an intermediate offormula (VI). Said intermediate of formula (VI) can then be reacted withan intermediate of formula (VII) wherein W₃ represents a suitableleaving group, such as for example halo, e.g. bromo and wherein R^(x)and R^(y) represent C₁₋₄alkyl, and R^(z) represent C₁₋₄alkyl or phenyl,for instance R^(x) and R^(y) represent CH₃ and R^(z) represents C(CH₃)₃or phenyl, in the presence of a suitable base, such as for examplesodium hydride, and a suitable solvent, such as for exampleN,N-dimethylformamide or N,N-dimethylacetamide, resulting in anintermediate of formula (VIII). Intermediates of formula (VIII) orintermediates of formula (VIII) wherein the R¹ substituent carries asuitable protective group can also be prepared by reacting anintermediate of formula (IV) or an intermediate of formula (IV) whereinthe R¹ substituent carries a suitable protective group with anintermediate of formula (XXIII′) wherein R^(3d′) represent—C₁₋₆alkyl-O—Si(R^(x))(R^(y))(R^(z)) in the presence of a suitablecatalyst, such as for example palladium (II) acetate, a suitable ligand,such as for example racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl,a suitable base, such as for example Cs₂CO₃, and a suitable solvent,such as for example 1,2-dimethoxyethane. Intermediates of formula (VIII)can be converted into a compound of formula (I) wherein R³ represents—C₁₋₆alkyl-OH, said compounds being represented by formula (Ia-a) orcompounds of formula (I-a) wherein the R¹ substituent carries a suitableprotective group, by reaction with tetrabutylammonium fluoride in thepresence of a suitable solvent, such as for example tetrahydrofuran.This type of reaction can also be performed in the presence of asuitable acid, such as for example acetic acid or HCl, and a suitablesolvent, such as for example tetrahydrofurane or dioxane. Alternatively,an intermediate of formula (VI) can react with an intermediate offormula (VII′) wherein W₃ represents a suitable leaving group, such asfor example halo, e.g. bromo and the like, in the presence of a suitablebase, such as for example sodium hydride, and a suitable solvent, suchas for example N,N-dimethylformamide or N,N-dimethylacetamide, resultingin an intermediate of formula (XXV) which can then be deprotected in thepresence of a suitable acid, such as for example HCl, and a suitablesolvent, such as for example an alcohol, e.g. methanol or isopropanol,to give a compound of formula (Ia-a). The compounds of formula (Ia-a) orcompounds of formula (Ia-a) wherein the R¹ substituent carries asuitable protective group can be reacted with methanesulfonyl chloridein the presence of a suitable base, such as for example triethylamine,diisopropylethanamine or N,N-dimethyl-4-aminopyridine, and a suitablesolvent, such as for example dichloromethane or tetrahydrofuran, toresult in an intermediate of formula (IX) (mesylate derivative) or anintermediate of formula (IX′) (chloride derivative) or intermediates offormula (IX) or (IX′) wherein the R¹ substituent carries a suitableprotective group. Intermediates of formula (IX) or (IX′) can then bereacted with an intermediate of formula (X) to obtain a compound offormula (Ia) wherein R³ represents C₁₋₆alkyl substituted with NR¹⁰R¹¹,said compounds being represented by formula (Ia-b) or compounds offormula (Ia-b) wherein the R¹ substituent carries a suitable protectivegroup. This reaction may optionally be performed in the presence of asuitable base, such as for example triethylamine, K₂CO₃, Na₂CO₃ orsodium hydride and optionally a suitable solvent, such as for exampleacetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide,1-methyl-pyrrolidinone, a suitable alcohol, e.g. 1-butanol and the like.This type of reaction can also be performed with a suitable salt of theintermediate of formula (X), e.g. HCl salt of intermediate of formula(X), or may be performed in the presence of potassium iodide. In thisway compounds wherein R³ represents iodoC₁₋₆alkyl can be obtained.Compounds of formula (Ia-b) wherein the R¹ substituent carries asuitable protective group can be converted in a compound of formula(Ia-b) by reaction with a suitable acid, such as for exampletrifluoroacetic acid, in the presence of a suitable solvent, such as forexample dichloromethane.

Intermediates of formula (IX) can also react with a suitable nitrogencontaining ring within the definition of R⁹, said ring being representedby formula (XXI) or a suitable salt of an intermediate of formula (XXI),in the presence of a suitable solvent, such as for example acetonitrile,1-methyl-2-pyrrolidinone, or an alcohol, e.g. 1-butanol, optionally inthe presence of potassium iodide or a suitable base, such as for exampleNa₂CO₃, K₂CO₃ or triethylamine, resulting in a compound of formula(Ia-d). Intermediates of formula (IX) can also react with anintermediate of formula (X-a) wherein P represents a suitable protectivegroup, such as for example —C(═O)—O—C(CH₃)₃, in the presence of asuitable base, such as for example sodium hydride, and a suitablesolvent, such as for example dimethylacetamide, resulting in anintermediate of formula (XXX) which can be deprotected to a compound offormula (Ia-b-1) in the presence of a suitable acid, such as for exampleHCl or trifluoroacetic acid, and a suitable solvent, such as for exampledichloromethane or an alcohol, e.g. methanol. Intermediates of formula(XXX) can also be prepared by reacting an intermediate of formula (VI)with an intermediate of formula W₆—C₁₋₆alkyl-NR¹⁰P wherein W₆ representsa suitable leaving group, such as for example halo, e.g. bromo and thelike, or —O—S(═O)₂—CH₃, and P is as defined above, in the presence of asuitable base, such as for example sodium hydride, and a suitablesolvent, e.g. N,N-dimethylformamide or N,N-dimethylacetamide.Alternatively compounds of formula (Ia-d) or (Ia-b-1) can also beprepared by reacting respectively an intermediate of formula (VI) withan intermediate of formula W₆—C₁₋₆alkyl-N cycle or W₆—C₁₋₆alkyl-NHR¹⁰wherein W₆ is as defined above.

Intermediates of formula (VI) can react with W₆—R^(3d) wherein W₆represents a suitable leaving group, such as for example halo, e.g.bromo and the like, or —O—S(═O)₂—CH₃ or p-toluenesulfonate, and R^(3d)represents optionally substituted C₁₋₆alkyl, such as for example—CH₂—C₃H₅, in the presence of a suitable base, such as for examplesodium hydride or Cs₂CO₃, and a suitable solvent, such as for exampleN,N-dimethylformamide, N,N-dimethylacetamide or acetonitrile, resultingin a compound of formula (Ia-c). W₆—R^(3d) can also be used in anappropriate salt form, e.g. a hydrochloric acid salt of W₆—R^(3d). Inthis way, compounds of formula (Ia-c) wherein R³ represents—S(═O)₂—N(CH₃)₂ can also be prepared by reacting an intermediate offormula (VI) with dimethylsulfamoyl chloride, in the presence of asuitable base, such as for example NaH, and a suitable solvent, such asfor example N,N-dimethylformamide. This type of reaction can also beused to prepare an intermediate wherein the R^(3d) moiety is protectedby an appropriate protective group, such as for example triphenylmethylor —CH₂—O—CH₂—CH₂—Si(CH₃)₃, which can then be deprotected to a compoundof formula (Ia-c) in the presence of a suitable acid, such as forexample HCl or trifluoroacetic acid, in a suitable solvent, such as forexample dichloromethane or acetonitrile, or by reaction with a suitabledesilylating agent, such as for example tetrabutylammonium fluoride inthe presence of a suitable solvent, such as for example tetrahydrofuran.This type of reaction can also be performed in the presence of asuitable phase transfer agent, such as for example tetrabutylammoniumbromide, a suitable base, such as for example potassium hydroxide, and asuitable solvent, such as for example 2-methyl-tetrahydrofuran andwater.

Compounds of formula (Ia-c) wherein R^(3d) represents —CH₂—C(OH)(R′)(R″)wherein R′ represents optionally substituted C₁₋₄alkyl and R″ representshydrogen or optionally substituted C₁₋₄alkyl, said compounds beingrepresented by formula (Ia-c-1), can be prepared by reacting theintermediate of formula (VI) with an intermediate of formula (XXII) inthe presence of a suitable base, such as for example sodium hydride,Cs₂CO₃, or potassium hydroxide, and a suitable solvent, such as forexample N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile orwater.

Intermediates of formula (IV) can also react with an intermediate offormula (XXIII) in the presence of a suitable catalyst, such as forexample palladium (II) acetate or tris(dibenzylideneacetone)dipalladium(0), a suitable base, such as for example sodium tert-butoxide, asuitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine] or2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl, and a suitablesolvent, such as for example dioxane, resulting in a compound of formula(Ia-c).

Compounds of formula (Ia-b) wherein R¹¹ is C₁₋₆alkyl substituted withamino, said compounds being represented by formula (Ia-b-2), can also beprepared according to the following reaction Scheme 1A.

In Scheme 1A, a compound of formula (Ia-b-1) is reacted withN-(haloC₁₋₆alkyl)phthalimide in the presence of a suitable base, such asfor example potassium carbonate, and a suitable solvent, such as forexample acetonitrile, resulting in an intermediate of formula (XXXVI)which can be converted into a compound of formula (Ia-b-2) by reactionwith hydrazine in the presence of a suitable solvent, such as forexample an alcohol, e.g. ethanol.

Compounds of formula (Ia) wherein R³ represents optionally substitutedC₂₋₆alkynyl, said compounds being represented by formula (Ia-k), can beprepared according to reaction Scheme 1B.

In Scheme 1B, an intermediate of formula (VI) is reacted with anintermediate of formula W₁₁—R^(3e) wherein R^(3e) represents optionallysubstituted C₂₋₆alkynyl and W₁₁ represents a suitable leaving group suchas for example halo, e.g. chloro, or —O—S(═O)₂—CH₃, in the presence of asuitable base, such as for example NaH, and a suitable solvent, such asfor example N,N-dimethylformamide. The intermediate W₁₁—R^(3e) whereinW₁₁ represents —O—S(═O)₂—CH₃, can be prepared by reacting thecorresponding alcohol derivative with methanesulfonyl chloride in thepresence of a suitable base, such as for example triethylamine or4-dimethylaminopyridine, and a suitable solvent, such as for exampledichloromethane.

Compounds of formula (Ia-k), wherein R^(3e) represents C₂₋₆alkynylsubstituted with hydroxyl, said compounds being represented by formula(Ia-k-1), can be prepared according to the following reaction Scheme 1C.

In Scheme 1C, an intermediate of formula (VI) is reacted with anintermediate of formula (XXXVIII) in the presence of a suitable base,such as for example NaH, and a suitable solvent, such as for exampleN,N-dimethylformamide, resulting in an intermediate of formula (VIII′),which is converted into a compound of formula (Ia-k-1) by reaction witha suitable acid, such as for example trifluoroacetic acid, in thepresence of a suitable solvent, such as for example tetrahydrofuran.This reaction can also be performed with tetrabutyl ammonium fluoride inthe presence of a suitable solvent such as for example tetrahydrofuran.

Alternatively, instead of an intermediate of formula (XXXVIII),halo-C₂₋₆alkynyl-O—Si(R^(x))(R^(y))(R^(z)) can also be used.

Compounds of formula (Ia-k), wherein R^(3e) represents C₂₋₆alkynyl, saidcompounds being represented by formula (Ia-k-2), can be preparedaccording to the following reaction Scheme 1D.

In Scheme 1 D, a compound of formula (Ia-k-2) is prepared bydeprotecting an intermediate of formula (XXXXII) in the presence of asuitable base, such as for example K₂CO₃, and a suitable solvent, suchas for example an alcohol, e.g. methanol and the like. Said intermediateof formula (XXXXII) can be prepared by reacting an intermediate offormula (VI) with W₁₃—C₂₋₆alkynyl-Si(CH₃)₃ wherein W₁₃ is a suitableleaving group, such as for example halogen, in the presence of asuitable base, such as for example NaH, and a suitable solvent, such asfor example N,N-dimethylformamide.

Compounds of formula (Ia), wherein R³ represents ethyl substituted with—P(═O)(OC₁₋₆alkyl)₂, said compounds being represented by formula (Ia-l),can be prepared according to the following reaction Scheme 1E.

In scheme 1E, an intermediate of formula (VI) is reacted withdi(C₁₋₆alkyl)vinylphosphonate in the presence of a suitable catalyst,such as for example tri-N-butylphosphine, and a suitable solvent, suchas for example acetonitrile resulting in a compound of formula (Ia-l).

Intermediates of formula (VIII) can alternatively also be preparedaccording to the following reaction Scheme 2.

In Scheme 2, an intermediate of formula (XVII) is reacted with anintermediate of formula (VII) in the presence of a suitable base, suchas for example sodium hydride, and a suitable solvent, such as forexample N,N-dimethylformamide, resulting in an intermediate of formula(XVIII). The intermediate of formula (XVIII) can then be reacted with anintermediate of formula (III) in the presence of a suitable catalyst,such as for example Pd₂(dba)₃, a suitable base, such as for exampleK₃PO₄, a suitable ligand, such as for example2-dicyclohexylphosphino-2′,6′-dimethoxy-biphenyl, and a suitablesolvent, such as for example dioxane or water or mixtures thereof.

Intermediates of formula (VIII′) can be prepared according to thefollowing reaction Scheme 3.

In Scheme 3, an intermediate of formula (XVIII) is reacted with anintermediate of formula (XXXVII) in the presence of a suitable catalyst,such as for example tetrakis(triphenylphisphine)palladium (0), and asuitable solvent, such as for example toluene.

Intermediates of formula (VIII′) wherein D is a ring moiety containing anitrogen atom, as represented in Scheme 4, can be further reactedaccording to the following reaction Scheme 4.

In Scheme 4, the D′N moiety represents a D moiety wherein the D ringmoiety contains a nitrogen atom. Intermediates of formula (VIII′)wherein D represents D′NH, said intermediates being represented byformula (VIII′-a), can be converted into an intermediate of formula(VIII′-b) by reaction with W₁₂—C₁₋₆alkyl-halo wherein W₁₂ represents asuitable leaving group, such as for example halo, e.g. chloro, in thepresence of a suitable base, such as for example NaH, and a suitablesolvent, such as for example N,N-dimethylformamide. Said intermediatesof formula (VIII′-b) can be converted into an intermediate of formula(VIII′-c) by reaction with R⁶ in the presence of a suitable base, suchas for example K₂CO₃, and a suitable solvent, such as for exampleacetonitrile. When in an intermediate of formula (VIII′-c) the R⁶carries a hydroxyl group as in an intermediate of formula (VIII′-c-1),then said hydroxyl group can be protected by a suitable protective groupP, such as for example —O—C(═O)—C₁₋₆alkyl, by reaction withC₁₋₆alkyl-C(═O)—W₁₂, in the presence of a suitable base, such as forexample triethylamine, 4-dimethylaminopyridine, and a suitable solvent,such as for example dichloromethane, resulting in an intermediate offormula (VIII′-c-2) which can be converted into an intermediate offormula (XXXIX) by reaction with tetrabutylammonium fluoride in thepresence of a suitable solvent, such as for example tetrahydrofuran.Said intermediate of formula (XXXIX) can be converted into anintermediate of formula (XXXX) wherein R^(u) represents —SO₂CH₃, byreaction with methane sulfonyl chloride in the presence of a suitablebase, such as for example triethylamine, and a suitable solvent, such asfor example dichloromethane, which can be converted into an intermediateof formula (XXXXI) by reaction with an intermediate of formula (X) in asuitable solvent, such as for example acetonitrile. Said intermediate offormula (XXXXI) can then be deprotected into a compound of formula(Ia-b-4) in the presence of a suitable base, such as for example K₂CO₃,and a suitable solvent, such as for example an alcohol, e.g. methanoland the like. It is considered to be within the knowledge of the personskilled in the art to recognize for which other D ring moieties thedescribed reactions also apply.

Intermediates of formula (VIII′) can also be reacted to preparecompounds of the present invention according to the reaction schemes aspresented in Scheme 1. It is considered to be within the knowledge ofthe skilled person to recognize in which condition and for whichdefinitions of R¹ on the D ring moiety a protective group may beappropriate for the reactions to be carried out. For instance, ahydroxyl group within the definition of R¹ may be protected with a tert.butyldimethylsilyl moiety; a NH group within the definition of R¹ may beprotected with a —C(═O)—O—C(CH₃)₃ group.

It is also considered to be within the knowledge of the skilled personto recognize appropriate deprotection reactions.

Compounds of formula (Ia) wherein R³ represents optionally substitutedC₁₋₆alkyl, said compounds being represented by formula (Ia-c), can alsobe prepared according to the below reaction Scheme 5.

In Scheme 5, an intermediate of formula (XVII) is reacted with W₆—R^(3d)wherein W₆ represents a suitable leaving group, such as for examplehalo, e.g. bromo and the like, and R^(3d) represents optionallysubstituted C₁₋₆alkyl, such as for example —CH₂—C₃H₅, in the presence ofa suitable base, such as for example sodium hydride, and a suitablesolvent, such as for example N,N-dimethylformamide, resulting in anintermediate of formula (XIX). In a next step, the intermediate offormula (XIX) is reacted with an intermediate of formula (III) or(III-a) in the presence of a suitable catalyst, such as for exampletetrakis(triphenyl)phosphine palladium or Pd₂(dba)₃(tris(dibenzylideneacetone) dipalladium (0)), optionally a suitableligand, such as 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, asuitable base, such as for example Na₂CO₃ or K₃PO₄, and a suitablesolvent, such as for example ethylene glycol dimethylether or dioxane orwater. Or the intermediate of formula (XIX) is reacted with anintermediate of formula (XXXVII) in the presence of a suitable catalyst,such as for example tetrakis(triphenyl)phosphine palladium, and asuitable solvent, such as for example N,N-dimethylformamide or toluene.Or the intermediate of formula (XIX) is reacted with D-W, wherein Wrepresents a suitable leaving group, such as for example halo, e.g.bromo, iodod and the like, in the presence of a suitable catalyst, suchas for example tetrakis(triphenyl)phosphine palladium, ethylmagnesiumchloride, zinc chloride to generate in situ a reactive organometallicspecies, and a suitable solvent, such as for example tetrahydrofuran. Anintermediate of formula (XIX) can also react with a suitable ring moietyrepresented by D, e.g. imidazole or 4-methylimidazole or3-methylpyrazole or 2-methylimidazole, in the presence of a suitablecatalyst, such as for example tris(dibenzylideneacetone) dipalladium(0), a suitable ligand, such as for exampleRac-bis(diphenylphosphino)-1,1′-binaphthyl, in the presence of asuitable base, such as for example sodium tert-butoxide, and a suitablesolvent, such as for example toluene to obtain the corresponding finalcompound.

An intermediate of formula (XIX) can also react with1-(triisopropylsilyl)pyrrole-3-boronic acid, in the presence of asuitable catalyst, such as for example tetrakis(triphenyl)phosphinepalladium, a suitable base, such as for example sodium carbonate, or asuitable deprotective reagent, such as for example tetrabutylammoniumfluoride, to cleave C-Silicon bond, and a suitable solvent, such as forexample ethylene glycol dimethylether, to obtain a compound of formula(Ia-c-2). An intermediate of formula (XIX) can react with zinc cyanidein the presence of a suitable catalyst, such as for exampletetrakis(triphenyl)phosphine palladium, a suitable ligand, such as forexample triphenylphosphine, and a suitable solvent, such as for exampleacetonitrile. The resulting intermediate of formula (IXL) can react withsodium azide and ammonium chloride in the presence of a suitablesolvent, such as for example N,N-dimethylformamide, to obtain a compoundof formula (Ia-c-3). It is considered to be within the knowledge of theskilled person to recognize that instead of R^(3d), also a suitableprotected form of R^(3d) can be used.

Compounds of formula (Ia-c) can alternatively also be prepared accordingto the below reaction Scheme 6.

In Scheme 6, an intermediate of formula (IV) is reacted with R^(3d)—NH₂in the presence of a suitable catalyst, such as for example palladium(II) acetate, a suitable base, such as for example sodium tert-butoxide,and a suitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], resultingin an intermediate of formula (XX) which is reacted in a next step withan intermediate of formula (XIV) in the presence of a suitable catalyst,such as for example palladium (II) acetate or Pd₂(dba)₃(tris(dibenzylidene acetone) dipalladium (0)), a suitable ligand such asfor example 2-dicyclohexylphosphino-tris-isopropyl-biphenyl or1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], asuitable base, such as for example sodium tert-butoxide, and a suitablesolvent, such as for example ethylene glycol dimethylether.

Compounds of formula (I) wherein R³ represents optionally substitutedC₁₋₆alkyl, and wherein Y is E-D and E is other than a bond, saidcompounds being represented by formula (Ib) can be prepared according tothe below reaction Scheme 7.

In Scheme 7, an intermediate of formula (XIX) is reacted with D-NH₂ inthe presence of a suitable catalyst, such as for example palladium (II)acetate, a suitable base, such as for example sodium tert-butoxide, anda suitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], resultingin a compound of formula (Ib-1). Or an intermediate of formula (XIX) isreacted with D

CH, in the presence of a suitable catalyst, such as for exampledichlorobis(triphenylphosphine) palladium (II) and copperiodide, asuitable ligand, such as for example triphenylphosphine, a suitablebase, such as for example triethylamine, and a suitable solvent, such asfor example N,N-dimethylformamide to obtain a compound of formula(Ib-2). A compound of formula (Ib-2) can also be prepared by reacting anintermediate of formula (XLI) with D-W as defined above, in the presenceof a suitable catalyst, such as for exampledichlorobis(triphenylphosphine) palladium (II) and copperiodide, asuitable base, such as for example triethylamine, and a suitablesolvent, such as for example N,N-dimethylformamide and acetonitrile. Theintermediate of formula (XLI) can be prepared by reacting anintermediate of (XIX) with (trimethylsilyl)acetylene in the presence ofa suitable catalyst, such as for example dichlorobis(triphenylphosphine)palladium (II) and copperiodide, a suitable ligand, such as for exampletriphenylphosphine, a suitable base, such as for example triethylamine,and a suitable solvent, such as for example dimethylsulfoxide, followedby reacting the resulting intermediate of formula (XL) with potassiumcarbonate in a suitable solvent, such as for example an alcohol, e.g.methanol. The intermediate of formula (XLI) can also react with2-(4-morpholino)ethylazide, in the presence of a suitable catalyst, suchas for example copper iodide, a suitable base, such as for exampleN,N-diisopropylethylamine, and a suitable solvent, such as for exampletetrahydrofuran, to obtain a compound wherein E is a bond and D is2-(4-morpholino)ethyl-1-triazolyl. An intermediate of formula (XLI) canalso react with sodium azide and formaldehyde in the presence of asuitable catalyst, such as for example copper sulfate and sodium Lascorbate, and a suitable solvent, such as for example dioxane andacetic acid, to obtain a compound of formula (IA-c-4).

Compounds of formula (Ib) can also be prepared according to the belowreaction Scheme 7B.

In Scheme 7B, an intermediate of formula (XIX) is reacted with CO gaz,potassium acetate, in the presence of a suitable catalyst, such as forexample tetrakis(triphenyl)phosphine palladium, and a suitable solvent,such as for example dioxane. The resulting intermediate of formula(XLII) is reacted with D-(CR^(x)R^(y))_(s)—NH₂ in the presence ofsuitable peptide coupling reagents such as for example1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and1-hydroxybenzotriazole, a suitable base, such as for exampletriethylamine, and a suitable solvent, such as for example methylenechloride, to obtain a compound of formula (Ib-3). The intermediate offormula (XLII) can also react with D-H in the presence of suitablepeptide coupling reagents such as for example1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and1-hydroxybenzotriazole, a suitable base, such as for exampletriethylamine, and a suitable solvent, such as for example methylenechloride to obtain a compound of formula (Ib-4). An intermediate offormula (XIX) can also react with NH₃ in the presence of a suitablecatalyst such as for example Pd[P(o-tol)₃]₂, a suitable ligand such asfor example CyPF-t-Bu (Josiphos ligand), a suitable base such as forexample sodium tert-butoxide, a suitable solvent such as for example1,4-dioxane, to obtain intermediate (XLIII), which can react withD-COOH, in the presence of suitable peptide coupling reagents such asfor example 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideand 1-hydroxybenzotriazole, a suitable base, such as for exampletriethylamine, and a suitable solvent, such as for example methylenechloride to obtain a compound of formula (Ib-5).

Compounds of formula (I) wherein W is —NR³—, said compound beingrepresented by formula (Ic), and said R³ is C₁₋₆alkyl substituted with5-amino-1,3,4-oxadiazolyl can be prepared according to the belowreaction Scheme 8.

In Scheme 8, a compound of formula (Ic-1) is reacted with NH₂—NH₂ in thepresence of a suitable solvent, such as for example an alcohol, e.g.ethanol resulting in an intermediate of formula (XXXI) which is thenreacted in a next step with W₈—CN, wherein W₈ represents a suitableleaving group, such as for example halo, e.g. bromo, in the presence ofa suitable base, such as for example NaHCO₃, and a suitable solvent,such as for example water or dioxane.

Compounds of formula (Ic) wherein R³ is C₁₋₈alkyl substituted with3,3-dimethyl-morpholine can be prepared according to the below reactionScheme 8A.

In Scheme 8A, a compound of formula (Ic-3) is reacted with2-amino-2-methyl-1-propanol in the presence of a suitable base, such asfor example NaH and in the presence of a suitable solvent, such as forexample N,N-dimethylformamide resulting in an intermediate of formula(XXXII) of which the NH₂ moiety is protected by a suitable protectinggroup P, such as for example —C(═O)—O—C(CH₃)₃, by reaction with forinstance di-tert-butyl dicarbonate in the presence of a suitablesolvent, such as for example dioxane, and a suitable base, such as forexample NaHCO₃, resulting in an intermediate of formula (XXXIII). In anext step, said intermediate is reacted with methanesulfonyl chloride inthe presence of a suitable solvent, such as for example dichloromethane,and a suitable base, such as for example triethylamine resulting in anintermediate of formula (XXXIV) which is converted into an intermediateof formula (XXXV) by reaction with a suitable acid, such as for exampletrifluoroacetic acid, in the presence of a suitable solvent, such as forexample dichloromethane. The intermediate of formula (XXXV) is convertedinto a compound of formula (Ic-4) by reaction with a suitable base, suchas for example N,N-diisopropylethylamine and triethylamine in thepresence of a suitable solvent, such as for example an alcohol, e.g.methanol.

In general, compounds of formula (I) wherein Y represents —CR¹⁸═N—OR¹⁹,said compounds being represented by formula (Id), can be prepared as inScheme 9.

In Scheme 9, an intermediate of formula (XLIV) is reacted withtributyl(1-ethoxyvinyl)tin, in the presence of a suitable catalyst, suchas for example dichlorobis(triphenylphosphine) palladium (II) andoptionally in the presence of copperiodide and a suitable ligand, suchas for example triphenylphosphine, and in the presence of a suitablesolvent, such as for example N,N-dimethylformamide, followed by reactingthe resulting intermediate of formula (XLV) with a suitable acid, suchas for example hydrochloric acid, and a suitable solvent, such as forexample acetone. The obtained intermediate of formula (XLVI) is thenreacted with R¹⁹—O—NH₂ in the presence of a suitable base such as forexample pyridine, and a suitable solvent, such as for example analcohol, e.g. ethanol, resulting in a compound of formula (Id-1). Apreferred intermediate of formula (XLIV) is the intermediate of formula(XIX).

An intermediate of formula (XLVI) can also be converted into a compoundof formula (I) wherein E is a direct bond and D is 3-methyl-oxazole oroxazole, by reaction with 1-methyl-1-tosylmethyl isocyanide ortosylmethyl isocyanide, in the presence of a suitable base, such as forexample dipotassium carbonate, and a suitable solvent, such as forexample an alcohol, e.g. methanol.

In general, compounds of formula (I) wherein W is —C(R^(3a)R^(3b))—,said compounds being represented by formula (Ie) can be preparedaccording to the following reaction Scheme 10.

In scheme 10, a compound of formula (Ie-1) is prepared by reacting anintermediate of formula (XLVII) wherein W₁₅ represents a suitable group,such as for example halo, e.g. bromo and the like, withbis(pinacolato)diboron in the presence of a suitable catalyst, such asfor example PdCl₂, and a suitable ligand, such as for example1,1-bis(diphenylphosphino)ferrocene, in the presence of a base, such asfor example potassium acetate, and a suitable solvent, such as forexample dioxane, followed by reacting the resulting intermediate offormula (L) with an intermediate of formula (XLIX) wherein W₁₆represents a suitable leaving group, such as for example halo, e.g.chloro and the like, in the presence of a catalyst, such as for exampledichlorobis(triphenylphosphine)palladium, a suitable base, such as forexample Na₂CO₃, and a suitable solvent, such as for exampletetrahydrofuran.

Compounds of formula (Ie) can also be prepared according to thefollowing reaction Scheme 11.

In Scheme 11, an intermediate of formula (XLVII) is reacted with anintermediate of formula (LI) in the presence of isopropylmagnesiumchloride to prepare the magnesium chloride derivative of XLVII and asuitable solvent, such as for example tetrahydrofuran. An intermediateof formula (XLVII) can also react with N,O-dimethylhydroxylaminehydrochloride in the presence of a suitable catalyst, such as forexample Pd(Ph₃)₄, a suitable base, such as for example triethylamine,and a suitable solvent, such as for example toluene, to result in anintermediate of formula (XLVIIa) which can react with an intermediate offormula (XLVIIb) in the presence of a suitable solvent, such as forexample tetrahydrofuran, to result in a compound of formula (Ie-2).

Compounds of formula (Ie) can also be prepared according to thefollowing reaction Scheme 12.

In Scheme 12, intermediates of formula (XLVII) are reacted with anintermediate of formula (LII) in the presence of a suitable catalyst,such as for example palladium(II)acetate, a suitable base, such as forexample potassium acetate, and tetrabutylammonium bromide as a phasetransfer agent, and a suitable solvent, such as for exampleN,N-dimethylformamide, to give a compound of formula (Ie-3). Compoundsof formula (Ie-3) can also be prepared by reacting an intermediate offormula (XLVII) with an intermediate of formula (LIV) in the presence ofa suitable catalyst, such as for example palladium(II)acetate, asuitable ligand, such as for example tri-o-tolylphosphine, a suitablebase, such as for example triethylamine, and a suitable solvent, such asfor example acetonitrile, resulting in an intermediate of formula(LIII), which can then be reacted with an intermediate of formula (XIV)wherein W₅ represents a suitable leaving group, such as for examplehalo, e.g. bromo, in the presence of a suitable catalyst, such as forexample palladium(II)acetate, a suitable base, such as for examplepotassium acetate, and tetrabutylammonium bromide as solid base, and asuitable solvent, such as for example N,N-dimethylformamide.

Compounds of formula (Ie) can also be prepared according to thefollowing reaction Scheme 13.

In Scheme 13, an intermediate of formula (LV) preferably in its saltform, e.g. HCl salt form, and (LI) are reacted with paraformaldehyde inthe presence of a suitable solvent, such as for example an alcohol, e.g.ethanol, then a suitable agent P—O—P to introduce a suitable protectivegroup P, such as for example —C(═O)—O—C(CH₃)₃ wherein P—O—P is(CH₃)₃C—O—C(═O)—O—C(═O)—O—C(CH₃)₃), is added in the presence of asuitable base, such as for example triethylamine, and a suitablesolvent, such as for example dichloromethane, resulting in anintermediate of formula (LVI), which is further reacted withp-toluenesulfonhydrazide in the presence of a suitable solvent, such asfor example an alcohol, e.g. ethanol, to give an intermediate of formula(LVII). The intermediate of formula (LVII) is then further reacted withan intermediate of formula (XLVII) in the presence of a suitablecatalyst, such as for example tris(dibenzylideneacetone)dipalladium (0),a suitable ligand, such as for example2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl a suitablebase, such as for example lithium tert-butoxide, and a suitable solvent,such as for example dioxane, resulting in an intermediate of formula(LVIII), the E and Z isomers of which can be separated by appropriateseparation techniques such as column chromatography. The intermediate offormula (LVIII) can then be converted into a compound of formula (Ie-4)by deprotection in the presence of a suitable acid, such as for exampleHCl, and a suitable solvent, such as for example an alcohol, e.g.methanol. A compound of formula (Ie-5) is prepared by reacting anintermediate of formula (LX) with p-toluenesulfonhydrazide in thepresence of a suitable acid, such as for example hydrochloric acid, anda suitable solvent, such as for example diethylether and water,resulting in an intermediate of formula (LIX), the E and Z isomers ofwhich can be separated by appropriate separation techniques such ascolumn chromatography. The intermediate of formula (LIX) can then bereacted with an intermediate of formula (XLVII) in the presence of asuitable catalyst, such as for exampletris(dibenzylideneacetone)dipalladium (0), a suitable ligand, such asfor example 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyla suitable base, such as for example lithium tert-butoxide, and asuitable solvent, such as for example dioxane, resulting in a compoundof formula (Ie-5). A compound of formula (Ie-6) is prepared by reactingan intermediate of formula (LXI) with a suitable reducing agent, such asfor example diisobutylaluminum hydride, and a suitable solvent, such asfor example tetrahydrofuran. The intermediate of formula (LXI) isprepared by reacting an intermediate of formula (XLVII) with anintermediate of formula (LXII) in the presence of a suitable catalyst,such as for example palladium(II)acetate, a suitable ligand, such as forexample tri-o-tolylphosphine, a suitable base, such as for exampletriethylamine, and a suitable solvent, such as for example acetonitrile.Intermediates of formula (LXI) can also be prepared by reacting acompound of formula (Ie-1) with triethylphosphonoacetate in the presenceof a suitable base, such as for example sodium hydride, and a suitablesolvent, such as for example tetrahydrofuran.

Compounds of formula (Ie) can also be prepared according to thefollowing reaction Scheme 14.

In Scheme 14, a compound of formula (Ie-6) is reacted with a leavinggroup introducing agent, such as for example methanesulfonyl chloride,in the presence of a suitable base, such as for example triethylamine,and a suitable solvent, such as for example dichloromethane, resultingin an intermediate of formula (LXIII) wherein W₁₇ represents a suitableleaving group, such as for example halo, e.g. chloro, which is thenfurther reacted with NHR¹¹ in the presence of a suitable solvent, suchas for example acetonitrile, to give a compound of formula (Ie-4).

Compounds of formula (Ie) can also be prepared according to thefollowing reaction Scheme 15.

In Scheme 15, a compound of formula (Ie-7) is prepared by reacting anintermediate of formula (LXI) with magnesium in the presence of asuitable solvent, such as for example tetrahydrofuran and an alcohol,e.g. methanol and the like. A compound of formula (Ie-8) is prepared byreacting an intermediate of formula (LXIV) with potassium cyanide in thepresence of a suitable solvent, such as for exampleN,N-dimethylformamide. The intermediate of formula (LXIV) is prepared byreacting a compound of formula (Ie-9) with methanesulfonyl chloride inthe presence of a suitable base, such as for example triethylamine, anda suitable solvent, such as for example acetonitrile. (Ie-9) can beprepared by reduction of (Ie-6) for example using LiAlH₄, in an aproticsolvent such as THF. The intermediate of formula (LXIV) is convertedinto a compound of formula (Ie-10) by reaction with HR⁹ in the presenceof a suitable base, such as for example sodium hydride, and a suitablesolvent, such as for example N,N-dimethylformamide. Compounds of formula(Ie-7) can also be prepared by reacting a compound of formula (Ie-9)with lithiumaluminiumhydride in the presence of a suitable solvent, suchas for example tetrahydrofuran.

Compounds of formula (Ie) can also be prepared according to thefollowing reaction Scheme 16.

In Scheme 16, a compound of formula (Ie-1) is reacted withtrimethylsulphoxonium iodide in the presence of a suitable base, such asfor example potassium tert butoxide, and a suitable solvent, such as forexample dimethoxymethane and dimethylsulfoxide resulting in anintermediate of formula (LXV), which can be converted into a compound offormula (Ie-11) by reaction with NHR¹⁰R¹¹ in the presence of a suitablesolvent, such as for example an alcohol, e.g. ethanol and the like.

Compounds of formula (Ie) can also be prepared according to thefollowing reaction Scheme 17.

In Scheme 17, an intermediate of formula (XIV) as defined above, and(LXVI) wherein P represents a suitable protective group as definedabove, is reacted with butyllithium in hexane in the presence of asuitable solvent, such as for example tetrahydrofuran, diethylether ormixtures thereof resulting in an intermediate of formula (LXVII), whichis further reacted with p-toluenesulfonhydrazide in the presence of asuitable solvent, such as for example an alcohol, e.g. ethanol, to givean intermediate of formula (LXVIII). The intermediate of formula(LXVIII) is then further reacted with an intermediate of formula (XLVII)in the presence of a suitable catalyst, such as for exampletris(dibenzylideneacetone)dipalladium (0), a suitable ligand, such asfor example2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl, a suitablebase, such as for example lithium tert-butoxide, and a suitable solvent,such as for example dioxane, resulting in an intermediate of formula(LXIX). The intermediate of formula (LXIX) is then converted into anintermediate of formula (LXX) by hydrogenation in the presence of asuitable catalyst, such as for example palladium on charcoal, and asuitable solvent, such as for example an alcohol, e.g. methanol. Theintermediate of formula (LXX) can then be converted into a compound offormula (Ie-12) by reaction with a suitable acid, such as for examplehydrochloric acid, in the presence of a suitable solvent, such as forexample an alcohol, e.g. methanol.

As already shown above, compounds of formula (I) or some of theabove-described intermediates can be prepared by deprotecting thecorresponding protected compounds. Other protection-deprotectionreactions are shown in the following reaction Scheme 18.

In Scheme 18, the Y′N moiety represents an -E-D moiety wherein the Dring moiety contains a nitrogen atom. Compounds of formula (I) whereinR¹ represents hydroxyC₁₋₆alkyl can be prepared by deprotecting anintermediate of formula (XXVI) in the presence of a suitable acid, suchas for example HCl or trifluoroacetic acid, or a suitable de-silylatingagent, such as for example tetrabutyl ammonium fluoride, and a suitablesolvent, such as an alcohol, e.g. methanol, or tetrahydrofuran (step 2).Intermediates of formula (XXVI) can be prepared by reacting a compoundof formula (I) wherein R¹ is hydrogen with an intermediate of formula(XXIV) wherein W₉ represents a suitable leaving group, such as forexample halo, e.g. bromo and the like, and P represents a suitableprotective group, such as for example —Si(CH₃)₂(C(CH₃)₃) or

in the presence of a suitable base, such as for example sodium hydrideor K₂CO₃, and a suitable solvent, such as for exampleN,N-dimethylformamide or acetonitrile (step 1). Compounds of formula (I)wherein Fe represents C₁₋₆alkyl substituted with —C(═O)—R⁶ wherein R⁶ isan appropriate nitrogen containing ring linked to the C(═O) moiety viathe nitrogen atom can be prepared by reacting an intermediate of formula(XXIX) with an intermediate of formula (XXI) in the presence of suitablepeptide coupling reagents such as, 1-hydroxy-benzotriazole and1-(3-dimethylaminopropyl)-3-ethyl carbodiimide HCl (step 5).Intermediates of formula (XXIX) can be prepared by reacting anintermediate of formula (XXVIII) with LiOH in the presence of a suitablesolvent, such as for example tetrahydrofuran or water (step 4).Intermediates of formula (XXVIII) can be prepared by as depicted in step3 with an intermediate of formula (XXVII) wherein W₉ is as definedabove, in the presence of a suitable base, such as for example sodiumhydride, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Step 6 depicts the preparation of compounds of formula (I) starting froman intermediate of formula (XXIX) by reaction with NHR⁴R⁵ in thepresence of suitable peptide coupling reagents such as1-hydroxy-benzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl and a suitable base, such as triethylamine, and asuitable solvent, such as for example dichloromethane.

Further protection-deprotection reactions can also be used as outlinedin the following reaction Scheme 19.

In Scheme 19, the following reaction conditions apply:

1; in the presence of a suitable base, such as for example sodiumhydride, and a suitable solvent, such as for exampleN,N-dimethylformamide.

2: in the presence of a suitable catalyst, such as for example palladium(II)acetate, a suitable base, such as for example sodium tert-butoxide,a suitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], and asuitable solvent, such as for example dioxane or ethylene glycoldimethylether.1a; in the presence of a suitable base, such as for example sodiumhydride, and a suitable solvent, such as for exampleN,N-dimethylformamide, followed by reduction with H₂ and Raney nickel,in a suitable alcohol,2a: in the presence of a suitable catalyst, such as for examplepalladium (II)acetate, a suitable base, such as for example sodiumtert-butoxide, a suitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], and asuitable solvent, such as for example dioxane or ethylene glycoldimethylether.3: in the presence of a suitable catalyst, such as for example palladium(II)acetate, a suitable base, such as for example sodium tert-butoxide,a suitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], and asuitable solvent, such as for example dioxane or ethylene glycoldimethylether.4: in the presence of a suitable base, such as for exampletriethylamine, and a suitable solvent, such as for exampledichloromethane.5: in the presence of a suitable base, such as for example K₂CO₃, and asuitable solvent, such as for example 1-methyl-2-pyrrolidinone.6: in the presence of hydrazine monohydrate, and a suitable solvent,such as for example an alcohol, e.g. ethanol.7: in the presence of a suitable base, such as for example K₂CO₃, and asuitable solvent, such as for example tetrahydrofuran.

It is considered to be within the knowledge of the person skilled in theart to recognize in which condition and on which part of the molecule aprotective group may be appropriate. For instance, protective group onthe R¹ substituent or on the D moiety, or protective group on the R³substituent or on the R² substituent or combinations thereof. Theskilled person is also considered to be able to recognize the mostfeasible protective group, such as for example —C(═O)—O—C₁₋₄alkyl or

or O—Si(CH₃)₂(C(CH₃)₃) or —CH₂—O—CH₂CH₂—O—CH₃ or—CH₂—O—CH₂—CH₂—Si(CH₃)₃. The skilled person is also considered to beable to recognize the most feasible deprotection reaction conditions,such as for example suitable acids, e.g. trifluoroacetic acid,hydrochloric acid, or suitable salts, such as for exampletetrabutylammonium fluoride. Reference herefore is also made to theexamples described in the Experimental Part hereinafter.

The skilled person is also considered to be able to recognize that whenR¹ represents C(═O)-morpholinyl, said R¹ can be prepared from—C(═O)—NH—CH₂—CH₂—O—CH₂—CH₂—O—SO₂-4-methylphenyl, in the presence ofsodium hydride, and a suitable solvent, such as for exampleN,N-dimethylformamide. Or that when R¹ represents —NH—C(═O)-morpholinyl,said R¹ can be prepared from —NH—C(═O)—O—C(CH₃)₃ in the presence ofmorpholine, and a suitable solvent, such as for example1-methyl-2-pyrrolidinone. Or that when R¹ represents hydroxylC₁₋₆alkyl,e.g. —CH₂—CH₂—OH, said R¹ can be prepared from the correspondingalkoxycarbonyl intermediate, e.g. —CH₂—C(═O)—O—CH₂—CH₃, in the presenceof Dibal-H 1M in hexane, and a suitable solvent, such as for exampletetrahydrofuran.

The present invention also comprises deuterated compounds. Thesedeuterated compounds may be prepared by using the appropriate deuteratedintermediates during the synthesis process. For instance an intermediateof formula (IV-a)

can be converted into an intermediate of formula (IV-b)

by reaction with iodomethane-D3 in the presence of a suitable base, suchas for example cesium carbonate, and a suitable solvent, such as forexample acetonitrile.

The compounds of formula (I) may also be converted into each other viaart-known reactions or functional group transformations.

For instance, compounds of formula (I) wherein R¹ representstetrahydropyranyl can be converted into a compound of formula (I)wherein R¹ represents hydrogen, by reaction with a suitable acid, suchas for example HCl or trifluoroacetic acid, in the presence of asuitable solvent, such as for example dichloromethane, dioxane, or analcohol, e.g. methanol, isopropanol and the like.

Compounds of formula (I) wherein R¹ or R³ represent monohaloalkyl, canbe converted into a compound of formula (I) wherein R¹ or R³ representC₁₋₆alkyl substituted with a ring moiety as defined hereinabove by theintermediate of formula (XXI) and linked to the C₁₋₆alkyl moiety by thenitrogen atom, by reaction with an intermediate of formula (XXI)optionally in the presence of a suitable base, such as for exampletriethylamine or K₂CO₃ or sodium hydride, and optionally in the presenceof a suitable solvent, such as for example acetonitrile,N,N-dimethylformamide or 1-methyl-2-pyrrolidinone. Compounds of formula(I) wherein R¹ or R³ represents C₁₋₆alkyl-OH, can be converted into acompound of formula (I) wherein R¹ or R³ represent C₁₋₆alkyl-F byreaction with diethylaminosulfur trifluoride in the presence of asuitable solvent, such as for example dichloromethane and in thepresence of catalytic amounts of an alcohol, such as for exampleethanol. Likewise, a compound of formula (I) wherein R¹ or R³ representC₁₋₆alkyl substituted with R⁶ or R⁹ wherein said R⁶ or R⁹ is substitutedwith OH, can be converted into a compound of formula (I) wherein R¹ orR³ represent C₁₋₆alkyl substituted with R⁶ or R⁹ wherein said R⁶ or R⁹is substituted with F, by reaction with diethylaminosulfur trifluoridein the presence of a suitable solvent, such as for exampledichloromethane.

Compounds of formula (I) wherein R¹ or R³ represent C₁₋₆alkylsubstituted with R⁶ or R⁹ wherein said R⁶ or R⁹ is substituted with—C(═O)—O—C₁₋₆alkyl, can be converted into a compound of formula (I)wherein R¹ or R³ represent C₁₋₆alkyl substituted with R⁶ or R⁹ whereinsaid R⁶ or R⁹ is substituted with —CH₂—OH, by reaction with LiAlH₄ inthe presence of a suitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith 1,3-dioxo-2H-isoindol-2-yl, can be converted into a compound offormula (I) wherein R³ represents C₁₋₆alkyl substituted with amino, byreaction with hydrazine monohydrate in the presence of a suitablesolvent, such as for example an alcohol, e.g. ethanol.

Compounds of formula (I) wherein R¹ or R³ represent C₁₋₆alkylsubstituted with amino, can be converted into a compound of formula (I)wherein R¹ or R³ represents C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, by reaction with Cl—S(═O)₂—C₁₋₆alkyl in thepresence of a suitable base, such as for example triethylamine, and asuitable solvent, such as for example dichloromethane.

Compounds of formula (I) wherein R¹ or R³ represents C₁₋₆alkylsubstituted with halo, can be converted into a compound of formula (I)wherein R¹ or R³ represent C₁₋₆alkyl substituted with NR⁴R⁵ or NR¹⁰R¹¹,by reaction with NHR⁴R⁵ or NHR¹⁰R¹¹, either using such amino in largeexcess or in the presence of a suitable base, such as for example K₂CO₃,and a suitable solvent, such as for example acetonitrile,N,N-dimethylacetamide or 1-methyl-pyrrolidinone.

Compounds of formula (I) wherein R¹ represents hydrogen, can beconverted into a compound of formula (I) wherein R¹ representspolyhaloC₁₋₆alkyl or polyhydroxyC₁₋₆alkyl or C₁₋₆alkyl or—S(═O)₂—NR¹⁴R¹⁵ or —S(═O)₂—C₁₋₆alkyl, by reaction withpolyhaloC₁₋₆alkyl-W or polyhydroxyC₁₋₆alkyl-W or C₁₋₆alkyl-W orW—S(═O)₂—NR¹⁴R¹⁵ or W—S(═O)₂—C₁₋₆alkyl, wherein W represents a suitableleaving group, such as for example halo, e.g. bromo and the like, in thepresence of a suitable base, such as for example sodium hydride or K₂CO₃or triethylamine or 4-dimethylamino-pyridine or diisopropylamine, and asuitable solvent, such as for example N,N-dimethylformamide oracetonitrile or dichloromethane. Compounds of formula (I) wherein R¹represents hydrogen can also be converted into a compound of formula (I)wherein R¹ represents C₁₋₆alkyl-OH, by reaction withW—C₁₋₆alkyl-O—Si(CH₃)₂(C(CH₃)₃) in the presence of a suitable base, suchas for example sodium hydride, and a suitable solvent, such as forexample N,N-dimethylformamide and, then followed by a reaction with asuitable desilylating agent such as tetrabutyl ammonium fluoride.

Compounds of formula (I) wherein R¹ represents hydrogen, can also beconverted into compound of formula (I) wherein R¹ represents ethylsubstituted with —S(═O)₂—C₁₋₆alkyl, by reaction withC₁₋₆alkyl-vinylsulfone, in the presence of a suitable base, such as forexample triethylamine, and a suitable solvent, such as for example analcohol, e.g. methanol or by reaction with C₁₋₆alkyl-2-bromoethylsulfonein the presence of a suitable deprotonating agent, such as for exampleNaH, and a suitable solvent, such as for example dimethylformamide.

Compounds of formula (I) wherein R¹ represents hydrogen can also beconverted into a compound of formula (I) wherein R¹ represents—CH₂—CHOH—CH₂

by reaction with

in the presence of a suitable base, such as for example sodium hydride,and a suitable solvent, such as for example N,N-dimethylformamide,wherein

represents a suitable nitrogen containing ring within the definition ofR⁶.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyl substitutedwith R⁶ wherein said R⁶ is substituted with —C(═O)—O—C₁₋₆alkyl or—S(═O)₂—NR¹⁴R¹⁵ or wherein R³ represents C₁₋₆alkyl substituted with R⁹wherein said R⁹ is substituted with —C(═O)—O—C₁₋₆alkyl or—S(═O)₂—NR¹⁴R¹⁵, can be converted into a compound of formula (I) whereinthe R⁶ or R⁹ is unsubstituted, by reaction with a suitable acid, such asfor example HCl and a suitable solvent, such as for example dioxane,acetonitrile or an alcohol, e.g. isopropylalcohol. Compounds of formula(I) wherein R¹ represents C₁₋₆alkyl substituted with R⁶ wherein said R⁶is a ring moiety comprising a nitrogen atom which is substituted with—CH₂—OH or wherein R³ represents C₁₋₆alkyl substituted with R⁹ whereinsaid R⁹ is a ring moiety comprising a nitrogen atom which is substitutedwith —CH₂—OH, can be converted into a compound of formula (I) whereinthe R⁶ or R⁹ is unsubstituted, by reaction with sodium hydroxide, in thepresence of a suitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyl substitutedwith R⁶ or R³ represents C₁₋₆alkyl substituted with R⁹, wherein said R⁶or said R⁹ is unsubstituted, can be converted into a compound of formula(I) wherein said R⁶ or said R⁹ is substituted with C₁₋₆alkyl, byreaction with W—C₁₋₆alkyl wherein W is as defined above, in the presenceof a suitable base. Such as for example sodium hydride, and a suitablesolvent, such as for example N,N-dimethylformamide.

Compounds of formula (I) wherein R¹ or R³ represent hydroxyC₁₋₆alkyl,can be converted into the corresponding carbonyl compound, by reactionwith dess-Martin-periodinane, in the presence of a suitable solvent,such as for example dichloromethane.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyl substitutedwith R⁶ or R³ represents C₁₋₆alkyl substituted with R⁹, wherein said R⁶or said R⁹ is substituted with C₁₋₆alkyl-halo, can be converted into acompound of formula (I) wherein said R⁶ or said R⁹ is substituted withC₁₋₆alkyl-CN, by reaction with sodium cyanide, in the presence of asuitable solvent, such as for example water or an alcohol, e.g. ethanol.

Compounds of formula (I) wherein R¹ represents C₁₋₆alkyl substitutedwith R⁶ wherein said R⁶ is unsubstituted or wherein R³ representsC₁₋₄alkyl substituted with R⁹ wherein said R⁹ is unsubstituted, can beconverted into a compound of formula (I) wherein R⁶ or R⁹ is substitutedwith CH₃ or CH(CH₃)₂, by reaction with formaldehyde or acetone andNaBH₃CN, in the presence of a suitable solvent, such as for exampletetrahydrofuran or an alcohol, e.g. methanol.

Compounds of formula (I) wherein R¹ contains a R⁶ substituentsubstituted with OH or wherein R³ contains a R⁹ substituent substitutedwith OH, can be converted into a compound of formula (I) wherein the R⁶or R⁹ substituent is substituted with C₁₋₆alkyloxy, by reaction withW—C₁₋₆alkyl, in the presence of a suitable base, such as for examplesodium hydride, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Compounds of formula (I) wherein R¹ contains a R⁶ substituentsubstituted with C₁₋₆alkyloxy or wherein R³ contains a R⁹ substituentsubstituted with C₁₋₆alkyloxy, can be converted into a compound offormula (I) wherein the R⁶ or R⁹ substituent is substituted with OH byreaction with a suitable acid, such as for example hydrochloric acid.Compounds of formula (I) wherein R¹ contains a R⁶ substituentsubstituted with halo or wherein R³ contains a R⁹ substituentsubstituted with halo can be converted into a compound of formula (I)wherein the R⁶ or R⁹ substituent is substituted with NR¹⁴R¹⁵ by reactionwith NHR¹⁴R¹⁵ in a suitable solvent, such as for example1-methyl-pyrrolidinone. Compounds of formula (I) wherein R³ representsC₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl, can be converted into acompound of formula (I) wherein R³ represents C₁₋₆alkyl substituted withCOOH, by reaction with LiOH in the presence of a suitable solvent, suchas for example tetrahydrofuran. Said compounds of formula (I) wherein R³represents C₁₋₆alkyl substituted with COOH, can be converted into acompound of formula (I) wherein R³ represents C₁₋₆alkyl substituted with—C(═O)—NH₂ or —C(═O)—NHCH₃ or —C(═O)NR¹⁹R¹¹, by reaction withNH(Si(CH₃)₃)₂ or MeNH₃ ⁺Cl⁻ or NHR¹⁰R¹¹ in the presence of suitablepeptide coupling reagents such as for example1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl and1-hydroxybenzotriazole, a suitable base, such as for exampletriethylamine and a suitable solvent such as for example dichloromethaneor N,N-dimethylformamide. Compounds of formula (I) wherein R³ representsC₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl, can also be convertedinto a compound of formula (I) wherein R³ represents C₁₋₆alkylsubstituted with 4,5-dihydro-1H-imidazolyl, by reaction under N₂ withethylenediamine and trimethylaluminium in the presence of a suitablesolvent, such as for example toluene and heptane. Compounds of formula(I) wherein R³ represents C₁₋₆alkyl substituted with COOH, can also beconverted into a compound of formula (I) wherein R³ represents C₁₋₆alkylsubstituted with —C(═O)—N(CH₃)(OCH₃) by reaction withdimethylhydroxylamine, in the presence of carbonyldiimidazole and asuitable solvent, such as for example dichloromethane.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith

can be converted into a compound of formula (I) wherein R³ representsC₁₋₆alkyl substituted with 2 OH's, by reaction with a suitable acid,such as for example trifluoroacetic acid, and a suitable solvent, suchas for example dioxane or water. These compounds of formula (I) whereinR³ represents C₁₋₆alkyl substituted with

can also be converted into a compound of formula (I) wherein R³represents C₁₋₆alkyl substituted with OH and NR¹⁰R¹¹, by reaction withNH₂R¹⁰R¹¹ optionally in salt form, such as for example NHR¹⁰R¹¹⁺Cl⁻,optionally in the presence of a suitable base, such as for examplesodium hydride or Na₂CO₃ or triethylamine, a suitable additive such asfor example KI, and in the presence of a suitable solvent, such as forexample N,N-dimethylformamide or an alcohol, e.g. 1-butanol or ethanol.

Compounds of formula (I) wherein R³ represents C₁₋₃alkyl substitutedwith —C(═O)—O—C₁₋₆alkyl, can be converted into a compound of formula (I)wherein R³ represents C₁₋₃alkyl substituted with —C(CH3)₂—OH, byreaction with iodomethane and Mg powder, in the presence of a suitablesolvent, such as for example diethylether or tetrahydrofuran.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith —C(═O)—O—C₁₋₆alkyl, can be converted into a compound of formula (I)wherein R³ represents C₁₋₆alkyl substituted with —OH, by reaction withLiAlH₄ in a suitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R³ represents C₁₋₅alkyl substitutedwith —OH, can be converted into a compound of formula (I) wherein R³represents C₁₋₅alkyl substituted with —O—C(═O)—C₁₋₆alkyl by reactionwith Cl—C(═O)—C1-6alkyl in the presence of a suitable base, such as forexample NaH, and a suitable solvent, such as for exampletetrahydrofuran.

Compounds of formula (I) wherein R³ represents —CH₂—CH═CH₂, can beconverted into a compound of formula (I) wherein R³ represents—CH₂—CHOH—CH₂—OH, by reaction with potassium permanganate, and asuitable solvent, such as for example acetone or water.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith —C(═O)—C₁₋₄alkyl, can be converted into a compound of formula (I)wherein R³ represents C₁₋₆alkyl substituted with —C(C₁₋₄alkyl)=N—OH, byreaction with hydroxylamine, in the presence of a suitable base, such asfor example pyridine, and a suitable solvent, such as for example analcohol, e.g. ethanol.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith NH₂, can be converted into a compound of formula (I) wherein R³represents C₁₋₆alkyl substituted with —NH—C(═O)—R⁶ or with—NH—C(═O)—C₁₋₆alkyl or with —NH—C(═O)-polyhydroxyC₁₋₆alkyl or with—NH—C(═O)-polyhaloC₁₋₆alkyl or with—NH—C(═O)-polyhydroxypolyhaloC₁₋₆alkyl, by reaction with thecorresponding COOH analogue, e.g. R⁶—COOH or CF₃—C(CH₃)(OH)—COOH and thelike, in the presence of suitable peptide coupling reagents such as1-hydroxy-benzotriazole and 1-(3-dimethylamino)propyl)carbodiimideoptionally in the presence of a suitable base, such as for exampletriethylamine. Said compounds of formula (I) wherein R³ representsC₁₋₆alkyl substituted with NH₂, can also be converted into a compound offormula (I) wherein R³ represents C₁₋₆alkyl substituted withNH—C(═O)—CF₃, by reaction with trifluoroacetic anhydride, in thepresence of a suitable base, such as for example triethylamine, and asuitable solvent, such as for example tetrahydrofuran. Said compounds offormula (I) wherein R³ represents C₁₋₆alkyl substituted with NH₂, canalso be converted into a compound of formula (I) wherein R³ representsC₁₋₆alkyl substituted with —NH-polyhaloC₁₋₆alkyl, e.g. —NH—CH₂—CH₂—F, byreaction with polyhaloC₁₋₆alkyl-W, with W as defined above, e.g.iodo-2-fluoroethane, in the presence of a suitable base, such as forexample K₂CO₃, and a suitable solvent, such as for exampleN,N-dimethylformamide or dioxane. Said compounds of formula (I) whereinR³ represents C₁₋₆alkyl substituted with NH₂ can also be converted intoa compound of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith —NH—R⁶ or —N(R⁶)₂ wherein R⁶ represents for example oxetane, byreaction with the appropriate R⁶ in the presence of a suitable reducingagent, such as for example sodium triacetoxyborohydride, a suitableacid, such as for example acetic acid, and a suitable solvent, such asfor example 1,2-dichloroethane.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith cyano, can be converted into a compound of formula (I) wherein R³represents C₁₋₆alkyl substituted with tetrazolyl by reaction with sodiumazide, and NH₄ ⁺Cl⁻ in the presence of a suitable solvent, such as forexample N,N-dimethylformamide.

Compounds of formula (I) wherein R³ represents —CH2-C≡CH, can beconverted into a compound of formula (I) wherein R³ represents

by reaction with ethyl azidoacetate in the presence of CuI and asuitable base, such as for example diisopropylamine, and a suitablesolvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R³ represents —CH2-C≡CH, can beconverted into a compound of formula (I) wherein R³ represents

by reaction with sodium azide and formaldehyde, in the presence of asuitable catalyst, such as for example CuSO₄ and sodium L ascorbate, asuitable acid, such as for example acetic acid, and a suitable solvent,such as for example dioxane.

Compounds of formula (I) wherein R³ represent C₂₋₆alkynyl, can beconverted into a compound of formula (I) wherein R³ representsC₂₋₆alkynyl substituted with R⁹, by reaction with W—R⁹ wherein W is asdefined above, in the presence of a suitable catalyst, such as forexample dichlorobis(triphenylphosphine)palladium, a suitable co-catalystsuch as CuI, a suitable base, such as for example triethylamine, and asuitable solvent, such as for example dimethylsulfoxide.

Compounds of formula (I) wherein R³ comprises R⁹ substituted with halo,can be converted into a compound of formula (I) wherein R³ comprises R⁹substituted with —NR¹⁴R¹⁵ by reaction with NHR¹⁴R¹⁵ in the presence of asuitable solvent, such as for example 1-methyl-2-pyrrolidinone.

Compounds of formula (I) wherein R³ comprises C₂₋₆alkynyl, can behydrogenated into a compound of formula (I) wherein R³ comprisesC₂₋₆alkyl in the presence of a suitable catalyst, such as for examplepalladium on charcoal, and a suitable solvent, such as for exampleethylacetate.

Compounds of formula (I) wherein R³ comprises C₂₋₆alkynyl, can behydrogenated into a compound of formula (I) wherein R³ comprisesC₂₋₆alkenyl in the presence of a suitable catalyst, such as for exampleLindlar catalyst, and a suitable solvent, such as for exampleethylacetate.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith —P(═O)(OC₁₋₆alkyl)₂ can be converted into a compound of formula (I)wherein R³ represents C₁₋₆alkyl substituted with —P(═O)(OH)₂ by reactionwith bromotrimethylsilane in the presence of a suitable solvent, such asfor example dichloromethane.

Compounds of formula (I) wherein the R⁹ substituent is substituted with═O, can be converted into the corresponding reduced R⁹ substituent byreaction with a suitable reducing agent, such as for example LiAlH₄ in asuitable solvent, such as for example tetrahydrofuran.

Compounds of formula (I) wherein R³ comprises —NHR¹⁹ can be convertedinto a compound of formula (I) wherein R³ comprises—NR¹⁹—(C═O)-optionally substituted C₁₋₆alkyl, by reaction with thecorresponding W—(C═O)-optionally substituted C₁₋₆alkyl wherein Wrepresents a suitable leaving group, such as for example halo, e.g.chloro and the like, in the presence of a suitable base, such as forexample triethylamine, and a suitable solvent, such as for exampleacetonitrile.

Compounds of formula (I) wherein R³ represents C₁₋₆alkyl substitutedwith NR¹⁰(benzyl) can be converted into a compound of formula (I)wherein R³ represents C₁₋₆alkyl substituted with NHR¹⁰, by reaction with1-chloroethylchloroformate in the presence of a suitable solvent, suchas for example dichloromethane

Compounds of formula (I) wherein R¹ represents unsubstituted piperidine,can be converted into a compound of formula (I) wherein R¹ represents1-methyl-piperidine, by reaction with iodomethane in the presence of asuitable base, such as for example potassium carbonate, and a suitablesolvent, such as for example acetonitrile.

Compounds of formula (I) wherein R¹ represents hydrogen can be convertedinto a compound of formula (I) wherein R¹ represents optionallysubstituted C₁₋₆alkyl, by reaction with optionally substitutedC₁₋₆alkyl-W wherein W represents a suitable leaving group, such as forexample halo, e.g. bromo and the like, in the presence of a suitablebase, such as for example potassium carbonate, and a suitable solvent,such as for example acetonitrile.

Compounds of formula (I) wherein R² represents halo, e.g. bromo, can beconverted into a compound of formula (I) wherein R² represents cyano, byreaction with zinc cyanide, in the presence of a suitable catalyst, suchas for example Pd₂(dba)₃ and a suitable ligand, such as for example1,1-bis(diphenylphosphino)ferrocene, in the presence of a suitablesolvent, such as for example N,N-dimethylformamide.

Said R² substituent being cyano can be converted into —CH₂—NH₂ byhydrogenation in the presence of NH₃ and Nickel.

Compounds of formula (I) wherein R² represents —OCH₃ can be convertedinto a compounds of formula (I) wherein R² represents —OH by reactionwith boron tribromide in the presence of a suitable solvent, such as forexample dichloromethane.

Compounds of formula (I) wherein R² represents —OH can be converted intoa compounds of formula (I) wherein R² represents —OCH₃ by reaction withmethyl iodine in the presence of a suitable base, such as for examplepotassium carbonate, and a suitable solvent, such as for exampleN,N-dimethylformamide.

Compounds of formula (I) wherein R² represents hydrogen, can beconverted into a compound of formula (I) wherein R² represents —CHOH—CF₃by reaction with trifluoroacetaldehyde methyl hemiketal.

Compounds of formula (I) wherein R^(3a) and R^(3b) are taken together toform ═O can be converted into a compound of formula (I) wherein R^(3a)is hydroxyl and R^(3b) is hydrogen in the presence of a suitablereducing agent, such as for example sodium borohydride, and a suitablesolvent, such as for example an alcohol, e.g. methanol.

Compounds of formula (I) wherein R^(3a) and R^(3b) are taken together toform ═O can also be converted into a compound of formula (I) whereinR^(3a) and R^(3b) are taken together to form ═—CN in the presence ofdiethyl cyanomethylphosphonate, a suitable base, such as for examplesodium hydride, and a suitable solvent, such as for exampletetrahydrofuran. The resulting compounds can be converted into acompound of formula (I) wherein R^(3a) is —CH₂—CN or —CH₂—C(═O)—NH₂ andR^(3b) is hydrogen, in the presence of sodium borohydride inpyridine/methanol.

For the conversion reactions, reference is also made to the examplesdescribed in the Experimental Part hereinafter.

A further aspect of the invention is a process for the preparation of acompound of formula (I) as defined herein, which process comprises:

(i) deprotecting a compound of formula (XXX) wherein P represents asuitable protective group, such as for example a butyloxycarbonyl-group(—CO₂C(CH₃)₃) in the presence of a suitable acid, such as for exampleHCl or trifluoroacetic acid;

or(ii) the reaction of a compound of the formula (IX) or (IX′):

or a protected form thereof, with an appropriately substituted amine ora reactive derivative thereof, such as for example NHR¹⁰R¹¹ (X), NHR¹⁰P(X-a) or

(XXI), for example in a sealed vessel, in the presence of a suitablebase, such as for example sodium hydride and/or in the presence orabsence of a solvent such as acetonitrile, N,N-dimethylformamide orN,N-dimethylacetamide; or(iii) the reaction of a compound of the formula (VI):

or a protected form thereof, with a compound of formulaW₆—C₁₋₆alkyl-NR¹⁰P wherein P represents a suitable protective group andW₆ represents a suitable leaving group, such as for example halo, e.g.bromo and the like, or —O—S(═O)₂—CH₃, in the presence of a suitablebase, such as for example sodium hydride, and a suitable solvent, e.g.N,N-dimethylformamide or N,N-dimethylacetamide, followed by removing Pand optionally removing any further protecting group present; or(iv) the reaction of a compound of the formula (VI):

or a protected thereof, with a compound of formula W₆—C₁₋₆alkyl-NHR¹⁰wherein W₆ represents a suitable leaving group, such as for examplehalo, e.g. bromo and the like, or —O—S(═O)₂—CH₃, in the presence of asuitable base, such as for example sodium hydride, and a suitablesolvent, e.g. N,N-dimethylformamide or N,N-dimethylacetamide; or thistype of reaction can also be performed in the presence of a suitablephase transfer agent, such as for example tetrabutylammonium bromide, asuitable base, such as for example potassium hydroxide, and a suitablesolvent, such as for example 2-methyl-tetrahydrofuran and water;(v) the reaction of a compound of formula (XXXVI)

with hydrazine in the presence of a suitable solvent, such as forexample an alcohol, e.g. ethanol;(vi) the reaction of a compound of formula (IX-1) wherein R^(u)represents —O—S(═O)₂—CH₃,

with an intermediate of formula (X) in the presence of a suitablesolvent, such as for example acetonitrile;(vii) the reaction of a compound of formula (VI)

with an intermediate of formula W₁₁—R^(3b) wherein R^(3b) representsoptionally substituted C₂₋₆alkynyl and W₁₁ represents a suitable leavinggroup such as for example halo, e.g. chloro, or —O—S(═O)₂—CH₃, in thepresence of a suitable base, such as for example NaH, and a suitablesolvent, such as for example N,N-dimethylformamide;(viii) the reaction of a compound of formula (VIII′) wherein R^(x) andR^(y) represent C₁₋₄alkyl, and R^(z) represent C₁₋₄alkyl or phenyl,

with a suitable acid, such as for example trifluoroacetic acid, in thepresence of a suitable solvent, such as for example tetrahydrofuran;(viii) deprotecting a compound of formula (XXXXII)

in the presence of a suitable base, such as for example K₂CO₃, and asuitable solvent, such as for example an alcohol, e.g. methanol and thelike;(ix) the reaction of a compound of formula (VI)

with di(C₁₋₆alkyl)vinylphosphonate in the presence of a suitablecatalyst, such as for example tri-N-butylphosphine, and a suitablesolvent, such as for example acetonitrile;(x) deprotecting a compound of formula (XXXXI) wherein the D′N moietyrepresents a D moiety wherein the D moiety contains a nitrogen atom

in the presence of a suitable base, such as for example K₂CO₃, and asuitable solvent, such as for example an alcohol, e.g. methanol and thelike;(xi) the reaction of a compound of formula (XIX) with a compound offormula (III) or (III-a)

in the presence of a suitable catalyst, such as for exampletetrakis(triphenyl)phosphine palladium or Pd₂(dba)₃(tris(dibenzylideneacetone) dipalladium (0)), a suitable ligand, such as2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl, a suitable base, suchas for example Na₂CO₃ or K₃PO₄, and a suitable solvent, such as forexample ethylene glycol dimethylether or dioxane or water;(xi-1) the reaction of a compound of formula (XIX) with a compound offormula (XXXVII)

in the presence of a suitable catalyst, such as for exampletetrakis(triphenyl)phosphine palladium, and a suitable solvent, such asfor example N,N-dimethylformamide or toluene.(xi-2) the reaction of a compound of formula (XIX) with D-W, wherein Wrepresents a suitable leaving group, such as for example halo, e.g.bromo, iodo and the like,

in the presence of a suitable catalyst, such as for exampletetrakis(triphenyl)phosphine palladium, ethylmagnesium chloride, zincchloride to generated in situ a reactive organometallic species, and asuitable solvent, such as for example tetrahydrofuran.(xii) the reaction of a compound of formula (XX) wherein R^(3a)represents optionally substituted C₁₋₆alkyl, with a compound of formula(XIV)

in the presence of a suitable catalyst, such as for example palladium(II) acetate or Pd₂(dba)₃ (tris(dibenzylidene acetone) dipalladium (0)),a suitable ligand such as for example2-dicyclohexylphosphino-tris-isopropyl-biphenyl or1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], asuitable base, such as for example sodium tert-butoxide, and a suitablesolvent, such as for example ethylene glycol dimethylether;(xiii) the reaction of a compound of formula (XXXI)

with W₈—CN, wherein W₈ represents a suitable leaving group, such as forexample halo, e.g. bromo, in the presence of a suitable base, such asfor example NaHCO₃, and a suitable solvent, such as for example water ordioxane;(xiv) the reaction of a compound of formula (XXXV)

with a suitable base, such as for example N,N-diisopropylethylamine andtriethylamine, in the presence of a suitable solvent, such as forexample an alcohol, e.g. methanol;(xv) deprotecting a compound of formula (XXVI) wherein P represents asuitable protective group such as for example —O—Si(CH₃)₂(C(CH₃)₃) or

and wherein Y′N represents an -E-D moiety wherein the D ring moietycontains a nitrogen atom

in the presence of a suitable acid, such as for example HCl ortrifluoroacetic acid, or a suitable de-silylating agent, such as forexample tetrabutyl ammonium fluoride, and a suitable solvent, such as analcohol, e.g. methanol, or tetrahydrofuran;(xvi) the reaction of a compound of formula (XXIX) wherein Y′Nrepresents an -E-D moiety wherein the D ring moiety contains a nitrogenatom, with a compound of formula (XXI)

in the presence of suitable peptide coupling reagents such as,1-hydroxy-benzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl;(xvii) the reaction of a compound of formula (XXIX) wherein Y′Nrepresents an -E-D moiety wherein the D ring moiety contains a nitrogenatom

with NHR⁴R⁵ in the presence of suitable peptide coupling reagents suchas 1-hydroxy-benzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl and a suitable base, such as triethylamine, and asuitable solvent, such as for example dichloromethane;(xviii) reacting the below compound

with NHR⁷R⁸ in the presence of a suitable base, such as for exampleK₂CO₃, and a suitable solvent, such as for example tetrahydrofuran;(xviii) deprotecting the below compound

in the presence of hydrazine monohydrate, and a suitable solvent, suchas for example an alcohol, e.g. ethanol;(xix) the reaction of a compound of formula (XLI) with D-W

in the presence of a suitable catalyst, such as for exampledichlorobis(triphenylphosphine) palladium (II) and copperiodide, asuitable base, such as for example triethylamine, and a suitablesolvent, such as for example N,N-dimethylformamide and acetonitrile;(xx) the reaction of a compound of formula (XIX) with D-NH₂

in the presence of a suitable catalyst, such as for example(tris(dibenzylideneacetone) dipalladium (0)), a suitable ligand, such asfor example 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene, a suitablebase, such as for example cesium carbonate, and a suitable solvent, suchas for example dioxane;(xxi) the reaction of a compound of formula (XIX) with D

CH

in the presence of a suitable catalyst, such as for exampledichlorobis(triphenylphosphine) palladium (II) and copperiodide, asuitable ligand, such as for example triphenylphosphine, a suitablebase, such as for example triethylamine, and a suitable solvent, such asfor example N,N-dimethylformamide(xxii) the reaction of a compound of formula (XLII) with D-H

in the presence of suitable peptide coupling reagents such as forexample 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and1-hydroxybenzotriazole, a suitable base, such as for exampletriethylamine, and a suitable solvent, such as for example methylenechloride(xxiii) the reaction of a compound of formula (XLII) withD-(CR^(x)R^(y))_(s)—NH₂

in the presence of suitable peptide coupling reagents such as forexample 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and1-hydroxybenzotriazole, a suitable base, such as for exampletriethylamine, and a suitable solvent, such as for example methylenechloride,(xxiv) the reaction of a compound of formula (XLIII) with D-COOH

in the presence of suitable peptide coupling reagents such as forexample 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride and1-hydroxybenzotriazole, a suitable base, such as for exampletriethylamine, and a suitable solvent, such as for example methylenechloride(xxv) the reaction of a compound of formula (XLVI) with R¹⁹—O—NH₂

in the presence of a suitable base such as for example pyridine, and asuitable solvent, such as for example an alcohol, e.g. ethanol,(xxvi) the reaction of a compound of formula (XLX) with a compound offormula (XLIX) wherein W₁₆ represents a suitable leaving group such asfor example halo, e.g. bromo and the like,

in the presence of a catalyst, such as for exampledichlorobis(triphenylphosphine)palladium, a suitable base, such as forexample Na₂CO₃, and a suitable solvent, such as for exampletetrahydrofuran

-   -   wherein the variables are as defined herein; and optionally        thereafter converting one compound of the formula (I) into        another compound of the formula (I).

A further embodiment is a process for synthesis of a compound of formula(VI) wherein:

a compound of formula (IV) is reacted with an intermediate of formula(V) in the presence of a suitable catalyst, such as for examplepalladium (II) acetate, a suitable base, such as sodium tert-butoxide orCs₂CO₃, a suitable ligand, such as for example1,1′-[1,1′-binaphthalene]-2,2′-diylbis[1,1-diphenylphosphine], and asuitable solvent or solvent mixture, such as for example dioxane orethylene glycol dimethylether and water.

A further embodiment is a process for synthesis of a compound of formula(VI) wherein:

the 6-aminoquinoline derivative is reacted with a halophenyl derivative,such as a bromo or iodo phenyl derivative, in the presence of a suitablecatalyst, such as for example tris(dibenzylideneacetone) dipalladium(0),a suitable base, such as Cs₂CO₃, a suitable ligand, such as for example2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl or xantphosin a suitable solvent or solvent mixture, such as for example2-methyl-2-propanol to result in an intermediate of formula (VI).

In a further embodiment the invention provides a novel intermediate. Inone embodiment the invention provides any of the novel intermediatesdescribed above. In another embodiment the invention provides a novelintermediate of formula (VI) or formula (IX).

In one embodiment, the present invention also relates to a compoundhaving the

-   -   or        following formula:

wherein E′ represents —(CR²²R²³)_(n)—, C₂₋₄alkenediyl optionallysubstituted with R²², C₂₋₄alkynediyl optionally substituted with R²²,—CO—(CR²²R²³)_(s)—, —(CR²²R²³)_(s)—CO—, —NR²²—(CR²²R²³)_(s)—,—(CR²²R²³)_(s)—NR²²—, —O—(CR²²R²³)_(s)—, —(CR²²R²³)_(s)—O—,—S(O)_(m)—(CR²²R²³)_(s)—, —(CR²²R²³)_(s)—S(O)_(m)—,—(CR²²R²³)_(s)—CO—NR²²—(CR²²R²³)_(s)— or—(CR²²R²³)_(s)—NR²²—CO—(CR²²R²³)_(s)—;wherein Y, D, R², and n are as defined for a compound of formula (I)above.Pharmaceutically Acceptable Salts, Solvates or Derivatives Thereof

In this section, as in all other sections of this application, unlessthe context indicates otherwise, references to formula (I) includereferences to all other sub-groups, preferences, embodiments andexamples thereof as defined herein.

Unless otherwise specified, a reference to a particular compound alsoincludes ionic forms, salts, solvates, isomers, tautomers, N-oxides,esters, prodrugs, isotopes and protected forms thereof, for example, asdiscussed below; preferably, the ionic forms, or salts or tautomers orisomers or N-oxides or solvates thereof; and more preferably, the ionicforms, or salts or tautomers or solvates or protected forms thereof,even more preferably the salts or tautomers or solvates thereof. Manycompounds of the formula (I) can exist in the form of salts, for exampleacid addition salts or, in certain cases salts of organic and inorganicbases such as carboxylate, sulphonate and phosphate salts. All suchsalts are within the scope of this invention, and references tocompounds of the formula (I) include the salt forms of the compounds. Itwill be appreciated that references to “derivatives” include referencesto ionic forms, salts, solvates, isomers, tautomers, N-oxides, esters,prodrugs, isotopes and protected forms thereof.

According to one aspect of the invention there is provided a compound asdefined herein or a salt, tautomer, N-oxide or solvate thereof.According to a further aspect of the invention there is provided acompound as defined herein or a salt or solvate thereof. References tocompounds of the formula (I) and sub-groups thereof as defined hereininclude within their scope the salts or solvates or tautomers orN-oxides of the compounds.

The salt forms of the compounds of the invention are typicallypharmaceutically acceptable salts, and examples of pharmaceuticallyacceptable salts are discussed in Berge et al. (1977) “PharmaceuticallyAcceptable Salts,” J. Pharm. Sci., Vol. 66, pp. 1-19. However, saltsthat are not pharmaceutically acceptable may also be prepared asintermediate forms which may then be converted into pharmaceuticallyacceptable salts.

Such non-pharmaceutically acceptable salts forms, which may be useful,for example, in the purification or separation of the compounds of theinvention, also form part of the invention.

The salts of the present invention can be synthesized from the parentcompound that contains a basic or acidic moiety by conventional chemicalmethods such as methods described in Pharmaceutical Salts: Properties,Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth(Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.Generally, such salts can be prepared by reacting the free acid or baseforms of these compounds with the appropriate base or acid in water orin an organic solvent, or in a mixture of the two; generally, nonaqueousmedia such as ether, ethyl acetate, ethanol, isopropanol, oracetonitrile are used. The compounds of the invention may exist as mono-or di-salts depending upon the pKa of the acid from which the salt isformed.

Acid addition salts may be formed with a wide variety of acids, bothinorganic and organic. Examples of acid addition salts include saltsformed with an acid selected from the group consisting of acetic,2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic),L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+)camphoric, camphor-sulphonic, (+)-(1S)-camphor-10-sulphonic, capric,caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric,ethane-1,2-disulphonic, ethanesulphonic, 2-hydroxyethanesulphonic,formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic,glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic),α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic,isethionic, lactic (e.g. (+)-L-lactic, (±)-DL-lactic), lactobionic,maleic, malic, (−)-L-malic, malonic, (±)-DL-mandelic, methanesulphonic,naphthalenesulphonic (e.g. naphthalene-2-sulphonic),naphthalene-1,5-disulphonic, 1-hydroxy-2-naphthoic, nicotinic, nitric,oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic,L-pyroglutamic, pyruvic, salicylic, 4-amino-salicylic, sebacic, stearic,succinic, sulphuric, tannic, (+)-L-tartaric, thiocyanic,toluenesulphonic (e.g. p-toluenesulphonic), undecylenic and valericacids, as well as acylated amino acids and cation exchange resins.

One particular group of salts consists of salts formed from acetic,hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic,succinic, maleic, malic, isethionic, fumaric, benzenesulphonic,toluenesulphonic, methanesulphonic (mesylate), ethanesulphonic,naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic,glucuronic and lactobionic acids. Another group of acid addition saltsincludes salts formed from acetic, adipic, ascorbic, aspartic, citric,DL-Lactic, fumaric, gluconic, glucuronic, hippuric, hydrochloric,glutamic, DL-malic, methanesulphonic, sebacic, stearic, succinic andtartaric acids.

If the compound is anionic, or has a functional group which may beanionic (e.g., —COOH may be —COO⁻), then a salt may be formed with asuitable cation. Examples of suitable inorganic cations include, but arenot limited to, alkali metal ions such as Na⁺ and K⁺, alkaline earthmetal cations such as Ca²⁺ and Mg²⁺, and other cations such as Al³⁺.Examples of suitable organic cations include, but are not limited to,ammonium ion (i.e., NH₄ ⁺) and substituted ammonium ions (e.g., NH₃R⁺,NH₂R₂ ⁺, NHR₃ ⁺, NR₄ ⁺).

Examples of some suitable substituted ammonium ions are those derivedfrom: ethylamine, diethylamine, dicyclohexylamine, triethylamine,butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine,benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, aswell as amino acids, such as lysine and arginine. An example of a commonquaternary ammonium ion is N(CH₃)₄ ⁺.

Where the compounds of the formula (I) contain an amine function, thesemay form quaternary ammonium salts, for example by reaction with analkylating agent according to methods well known to the skilled person.Such quaternary ammonium compounds are within the scope of formula (I).Compounds of the formula (I) containing an amine function may also formN-oxides. A reference herein to a compound of the formula (I) thatcontains an amine function also includes the N-oxide. Where a compoundcontains several amine functions, one or more than one nitrogen atom maybe oxidised to form an N-oxide. Particular examples of N-oxides are theN-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containingheterocycle. N-Oxides can be formed by treatment of the correspondingamine with an oxidizing agent such as hydrogen peroxide or a per-acid(e.g. a peroxycarboxylic acid), see for example Advanced OrganicChemistry, by Jerry March, 4^(th) Edition, Wiley Interscience, pages.More particularly, N-oxides can be made by the procedure of L. W. Deady(Syn. Comm. (1977), 7, 509-514) in which the amine compound is reactedwith m-chloroperoxybenzoic acid (MCPBA), for example, in an inertsolvent such as dichloromethane.

The compounds of the invention may form solvates, for example with water(i.e., hydrates) or common organic solvents. As used herein, the term“solvate” means a physical association of the compounds of the presentinvention with one or more solvent molecules. This physical associationinvolves varying degrees of ionic and covalent bonding, includinghydrogen bonding. In certain instances the solvate will be capable ofisolation, for example when one or more solvent molecules areincorporated in the crystal lattice of the crystalline solid. The term“solvate” is intended to encompass both solution-phase and isolatablesolvates. Non-limiting examples of suitable solvates include compoundsof the invention in combination with water, isopropanol, ethanol,methanol, DMSO, ethyl acetate, acetic acid or ethanolamine and the like.The compounds of the invention may exert their biological effects whilstthey are in solution.

Solvates are well known in pharmaceutical chemistry. They can beimportant to the processes for the preparation of a substance (e.g. inrelation to their purification, the storage of the substance (e.g. itsstability) and the ease of handling of the substance and are oftenformed as part of the isolation or purification stages of a chemicalsynthesis. A person skilled in the art can determine by means ofstandard and long used techniques whether a hydrate or other solvate hasformed by the isolation conditions or purification conditions used toprepare a given compound. Examples of such techniques includethermogravimetric analysis (TGA), differential scanning calorimetry(DSC), X-ray crystallography (e.g. single crystal X-ray crystallographyor X-ray powder diffraction) and Solid State NMR (SS-NMR, also known asMagic Angle Spinning NMR or MAS-NMR). Such techniques are as much a partof the standard analytical toolkit of the skilled chemist as NMR, IR,HPLC and MS. Alternatively the skilled person can deliberately form asolvate using crystallisation conditions that include an amount of thesolvent required for the particular solvate. Thereafter the standardmethods described above, can be used to establish whether solvates hadformed. Also encompassed by formula (I) are any complexes (e.g.inclusion complexes or clathrates with compounds such as cyclodextrins,or complexes with metals) of the compounds.

Furthermore, the compounds of the present invention may have one or morepolymorph (crystalline) or amorphous forms and as such are intended tobe included in the scope of the invention.

Compounds of the formula (I) may exist in a number of differentgeometric isomeric, and tautomeric forms and references to compounds ofthe formula (I) include all such forms. For the avoidance of doubt,where a compound can exist in one of several geometric isomeric ortautomeric forms and only one is specifically described or shown, allothers are nevertheless embraced by formula (I). Other examples oftautomeric forms include, for example, keto-, enol-, and enolate-forms,as in, for example, the following tautomeric pairs: keto/enol(illustrated below), imine/enamine, amide/imino alcohol,amidine/enediamines, nitroso/oxime, thioketone/enethiol, andnitro/aci-nitro.

Where compounds of the formula (I) contain one or more chiral centres,and can exist in the form of two or more optical isomers, references tocompounds of the formula (I) include all optical isomeric forms thereof(e.g. enantiomers, epimers and diastereoisomers), either as individualoptical isomers, or mixtures (e.g. racemic mixtures) of two or moreoptical isomers, unless the context requires otherwise. The opticalisomers may be characterised and identified by their optical activity(i.e. as + and − isomers, or d and l isomers) or they may becharacterised in terms of their absolute stereochemistry using the “Rand S” nomenclature developed by Cahn, Ingold and Prelog, see AdvancedOrganic Chemistry by Jerry March, 4^(th) Edition, John Wiley & Sons, NewYork, 1992, pages 109-114, and see also Cahn, Ingold & Prelog (1966)Angew. Chem. Int. Ed. Engl., 5, 385-415. Optical isomers can beseparated by a number of techniques including chiral chromatography(chromatography on a chiral support) and such techniques are well knownto the person skilled in the art. As an alternative to chiralchromatography, optical isomers can be separated by formingdiastereoisomeric salts with chiral acids such as (+)-tartaric acid,(−)-pyroglutamic acid, (−)-di-toluoyl-L-tartaric acid, (+)-mandelicacid, (−)-malic acid, and (−)-camphorsulphonic, separating thediastereoisomers by preferential crystallisation, and then dissociatingthe salts to give the individual enantiomer of the free base.

Where compounds of the formula (I) exist as two or more optical isomericforms, one enantiomer in a pair of enantiomers may exhibit advantagesover the other enantiomer, for example, in terms of biological activity.Thus, in certain circumstances, it may be desirable to use as atherapeutic agent only one of a pair of enantiomers, or only one of aplurality of diastereoisomers. Accordingly, the invention providescompositions containing a compound of the formula (I) having one or morechiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%,80%, 85%, 90% or 95%) of the compound of the formula (I) is present as asingle optical isomer (e.g. enantiomer or diastereoisomer). In onegeneral embodiment, 99% or more (e.g. substantially all) of the totalamount of the compound of the formula (I) may be present as a singleoptical isomer (e.g. enantiomer or diastereoisomer). When a specificisomeric form is identified (e.g. S configuration, or E isomer), thismeans that said isomeric form is substantially free of the otherisomer(s), i.e. said isomeric form is present in at least 55%, 60%, 65%,70%, 75%, 80%, 85%, 90%, 95%, 99% or more (e.g. substantially all) ofthe total amount of the compound of the invention.

The compounds of the invention include compounds with one or moreisotopic substitutions, and a reference to a particular element includeswithin its scope all isotopes of the element. For example, a referenceto hydrogen includes within its scope ¹H, ²H (D), and ³H (T). Similarly,references to carbon and oxygen include within their scope respectively¹³C and ¹⁴C and ¹⁶O and ¹⁸O. The isotopes may be radioactive ornon-radioactive. In one embodiment of the invention, the compoundscontain no radioactive isotopes. Such compounds are preferred fortherapeutic use. In another embodiment, however, the compound maycontain one or more radioisotopes. Compounds containing suchradioisotopes may be useful in a diagnostic context.

Esters such as carboxylic acid esters and acyloxy esters of thecompounds of formula (I) bearing a carboxylic acid group or a hydroxylgroup are also embraced by formula (I). In one embodiment of theinvention, formula (I) includes within its scope esters of compounds ofthe formula (I) bearing a carboxylic acid group or a hydroxyl group. Inanother embodiment of the invention, formula (I) does not include withinits scope esters of compounds of the formula (I) bearing a carboxylicacid group or a hydroxyl group. Examples of esters are compoundscontaining the group —C(═O)OR, wherein R is an ester substituent, forexample, a C₁₋₆ alkyl group, a heterocyclyl group, or a C₅₋₂₀ arylgroup, preferably a C₁₋₆ alkyl group. Particular examples of estergroups include, but are not limited to, —C(═O)OCH₃, —C(═O)OCH₂CH₃,—C(═O)OC(CH₃)₃, and —C(═O)OPh. Examples of acyloxy (reverse ester)groups are represented by —OC(═O)R, wherein R is an acyloxy substituent,for example, a C₁₋₇ alkyl group, a C₃₋₂₀ heterocyclyl group, or a C₅₋₂₀aryl group, preferably a C₁₋₇ alkyl group. Particular examples ofacyloxy groups include, but are not limited to, —OC(═O)CH₃ (acetoxy),—OC(═O)CH₂CH₃, —OC(═O)C(CH₃)₃, —OC(═O)Ph, and —OC(═O)CH₂Ph.

For example, some prodrugs are esters of the active compound (e.g., aphysiologically acceptable metabolically labile ester). By “prodrugs” ismeant for example any compound that is converted in vivo into abiologically active compound of the formula (I). During metabolism, theester group (—C(═O)OR) is cleaved to yield the active drug. Such estersmay be formed by esterification, for example, of any of the carboxylicacid groups (—C(═O)OH) in the parent compound, with, where appropriate,prior protection of any other reactive groups present in the parentcompound, followed by deprotection if required.

Examples of such metabolically labile esters include those of theformula —C(═O)OR wherein R is: C₁₋₆alkyl (e.g., -Me, -Et, -nPr, -iPr,-nBu, -sBu, -iBu, -tBu); C₁₋₆aminoalkyl [e.g., aminoethyl;2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C₁₋₇alkyl[e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl;1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonyloxyethyl;1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl;1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl;1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl;1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy)carbonyloxymethyl; 1-(4-tetrahydropyranyloxy)carbonyloxyethyl;(4-tetrahydropyranyl)carbonyloxymethyl; and1-(4-tetrahydropyranyl)carbonyloxyethyl]. Also, some prodrugs areactivated enzymatically to yield the active compound, or a compoundwhich, upon further chemical reaction, yields the active compound (forexample, as in antigen-directed enzyme pro-drug therapy (ADEPT),gene-directed enzyme pro-drug therapy (GDEPT) and ligand-directed enzymepro-drug therapy (LIDEPT) etc.). For example, the prodrug may be a sugarderivative or other glycoside conjugate, or may be an amino acid esterderivative.

Protein Tyrosine Kinases (PTK)

The compounds of the invention described herein inhibit or modulate theactivity of certain tyrosine kinases, and thus the compounds will beuseful in the treatment or prophylaxis, in particular the treatment, ofdisease states or conditions mediated by those tyrosine kinases, inparticular FGFR.

FGFR

The fibroblast growth factor (FGF) family of protein tyrosine kinase(PTK) receptors regulates a diverse array of physiologic functionsincluding mitogenesis, wound healing, cell differentiation andangiogenesis, and development. Both normal and malignant cell growth aswell as proliferation are affected by changes in local concentration ofFGFs, extracellular signalling molecules which act as autocrine as wellas paracrine factors. Autocrine FGF signalling may be particularlyimportant in the progression of steroid hormone-dependent cancers to ahormone independent state. FGFs and their receptors are expressed atincreased levels in several tissues and cell lines and overexpression isbelieved to contribute to the malignant phenotype. Furthermore, a numberof oncogenes are homologues of genes encoding growth factor receptors,and there is a potential for aberrant activation of FGF-dependentsignalling in human pancreatic cancer (Knights et al., Pharmacology andTherapeutics 2010 125:1 (105-117); Korc M. et al Current Cancer DrugTargets 2009 9:5 (639-651)).

The two prototypic members are acidic fibroblast growth factor (aFGF orFGF1) and basic fibroblast growth factor (bFGF or FGF2), and to date, atleast twenty distinct FGF family members have been identified. Thecellular response to FGFs is transmitted via four types of high affinitytransmembrane protein tyrosine-kinase fibroblast growth factor receptors(FGFR) numbered 1 to 4 (FGFR1 to FGFR4).

Disruption of the FGFR1 pathway should affect tumor cell proliferationsince this kinase is activated in many tumor types in addition toproliferating endothelial cells. The over-expression and activation ofFGFR1 in tumor-associated vasculature has suggested a role for thesemolecules in tumor angiogenesis.

A recent study has shown a link between FGFR1 expression andtumorigenicity in Classic Lobular Carcinomas (CLC). CLCs account for10-15% of all breast cancers and, in general, lack p53 and Her2expression whilst retaining expression of the oestrogen receptor. A geneamplification of 8p12-p11.2 was demonstrated in ˜50% of CLC cases andthis was shown to be linked with an increased expression of FGFR1.Preliminary studies with siRNA directed against FGFR1, or a smallmolecule inhibitor of the receptor, showed cell lines harbouring thisamplification to be particularly sensitive to inhibition of thissignalling pathway. Rhabdomyosarcoma (RMS) is the most common pediatricsoft tissue sarcoma likely results from abnormal proliferation anddifferentiation during skeletal myogenesis. FGFR1 is over-expressed inprimary rhabdomyosarcoma tumors and is associated with hypomethylationof a 5′ CpG island and abnormal expression of the AKT1, NOG, and BMP4genes. FGFR1 has also been linked to squamous lung cancer, colorectalcancer, glioblastoma, astrocytomas, prostate cancer, small cell lungcancer, melanoma, head and neck cancer, thyroid cancer, uterine cancer.

Fibroblast growth factor receptor 2 has high affinity for the acidicand/or basic fibroblast growth factors, as well as the keratinocytegrowth factor ligands. Fibroblast growth factor receptor 2 alsopropagates the potent osteogenic effects of FGFs during osteoblastgrowth and differentiation. Mutations in fibroblast growth factorreceptor 2, leading to complex functional alterations, were shown toinduce abnormal ossification of cranial sutures (craniosynostosis),implying a major role of FGFR signalling in intramembraneous boneformation. For example, in Apert (AP) syndrome, characterized bypremature cranial suture ossification, most cases are associated withpoint mutations engendering gain-of-function in fibroblast growth factorreceptor 2. In addition, mutation screening in patients with syndromiccraniosynostoses indicates that a number of recurrent FGFR2 mutationsaccounts for severe forms of Pfeiffer syndrome. Particular mutations ofFGFR2 include W290C, D321A, Y340C, C342R, C342S, C342W, N549H, K641R inFGFR2.

Several severe abnormalities in human skeletal development, includingApert, Crouzon, Jackson-Weiss, Beare-Stevenson cutis gyrata, andPfeiffer syndromes are associated with the occurrence of mutations infibroblast growth factor receptor 2. Most, if not all, cases of PfeifferSyndrome (PS) are also caused by de novo mutation of the fibroblastgrowth factor receptor 2 gene, and it was recently shown that mutationsin fibroblast growth factor receptor 2 break one of the cardinal rulesgoverning ligand specificity. Namely, two mutant splice forms offibroblast growth factor receptor, FGFR2c and FGFR2b, have acquired theability to bind to and be activated by atypical FGF ligands.

This loss of ligand specificity leads to aberrant signalling andsuggests that the severe phenotypes of these disease syndromes resultfrom ectopic ligand-dependent activation of fibroblast growth factorreceptor 2.

Genetic aberrations of the FGFR3 receptor tyrosine kinase such aschromosomal translocations or point mutations result in ectopicallyexpressed or deregulated, constitutively active, FGFR3 receptors. Suchabnormalities are linked to a subset of multiple myelomas and inbladder, hepatocellular, oral squamous cell carcinoma and cervicalcarcinomas. Accordingly, FGFR3 inhibitors would be useful in thetreatment of multiple myeloma, bladder and cervical carcinomas. FGFR3 isalso over-expressed in bladder cancer, in particular invasive bladdercancer. FGFR3 is frequently activated by mutation in urothelialcarcinoma (UC). Increased expression was associated with mutation (85%of mutant tumors showed high-level expression) but also 42% of tumorswith no detectable mutation showed over-expression, including manymuscle-invasive tumors. FGFR3 is also linked to endometrial and thyroidcancer.

Over expression of FGFR4 has been linked to poor prognosis in bothprostate and thyroid carcinomas. In addition a germline polymorphism(Gly388Arg) is associated with increased incidence of lung, breast,colon, liver (HCC) and prostate cancers. In addition, a truncated formof FGFR4 (including the kinase domain) has also been found to be presentin 40% of pituitary tumours but not present in normal tissue. FGFR4overexpression has been observed in liver, colon and lung tumours. FGFR4has been implicated in colorectal and liver cancer where expression ofits ligand FGF19 is frequently elevated. FGFR4 is also linked toastrocytomas, rhabdomyosarcoma.

Fibrotic conditions are a major medical problem resulting from abnormalor excessive deposition of fibrous tissue. This occurs in many diseases,including liver cirrhosis, glomerulonephritis, pulmonary fibrosis,systemic fibrosis, rheumatoid arthritis, as well as the natural processof wound healing. The mechanisms of pathological fibrosis are not fullyunderstood but are thought to result from the actions of variouscytokines (including tumor necrosis factor (TNF), fibroblast growthfactors (FGF's), platelet derived growth factor (PDGF) and transforminggrowth factor beta. (TGFβ) involved in the proliferation of fibroblastsand the deposition of extracellular matrix proteins (including collagenand fibronectin). This results in alteration of tissue structure andfunction and subsequent pathology.

A number of preclinical studies have demonstrated the up-regulation offibroblast growth factors in preclinical models of lung fibrosis. TGFβ1and PDGF have been reported to be involved in the fibrogenic process andfurther published work suggests the elevation of FGF's and consequentincrease in fibroblast proliferation, may be in response to elevatedTGFβ1. The potential therapeutic benefit of targeting the fibroticmechanism in conditions such as idiopathic pulmonary fibrosis (IPF) issuggested by the reported clinical effect of the anti-fibrotic agentpirfenidone. Idiopathic pulmonary fibrosis (also referred to asCryptogenic fibrosing alveolitis) is a progressive condition involvingscarring of the lung. Gradually, the air sacs of the lungs becomereplaced by fibrotic tissue, which becomes thicker, causing anirreversible loss of the tissue's ability to transfer oxygen into thebloodstream. The symptoms of the condition include shortness of breath,chronic dry coughing, fatigue, chest pain and loss of appetite resultingin rapid weight loss. The condition is extremely serious withapproximately 50% mortality after 5 years.

As such, the compounds which inhibit FGFR will be useful in providing ameans of preventing the growth or inducing apoptosis in tumours,particularly by inhibiting angiogenesis. It is therefore anticipatedthat the compounds will prove useful in treating or preventingproliferative disorders such as cancers. In particular tumours withactivating mutants of receptor tyrosine kinases or upregulation ofreceptor tyrosine kinases may be particularly sensitive to theinhibitors. Patients with activating mutants of any of the isoforms ofthe specific RTKs discussed herein may also find treatment with RTKinhibitors particularly beneficial.

Vascular Endothelial Growth Factor (VEGFR)

Chronic proliferative diseases are often accompanied by profoundangiogenesis, which can contribute to or maintain an inflammatory and/orproliferative state, or which leads to tissue destruction through theinvasive proliferation of blood vessels.

Angiogenesis is generally used to describe the development of new orreplacement blood vessels, or neovascularisation. It is a necessary andphysiological normal process by which vasculature is established in theembryo. Angiogenesis does not occur, in general, in most normal adulttissues, exceptions being sites of ovulation, menses and wound healing.Many diseases, however, are characterized by persistent and unregulatedangiogenesis. For instance, in arthritis, new capillary blood vesselsinvade the joint and destroy cartilage. In diabetes (and in manydifferent eye diseases), new vessels invade the macula or retina orother ocular structures, and may cause blindness. The process ofatherosclerosis has been linked to angiogenesis. Tumor growth andmetastasis have been found to be angiogenesis-dependent.

The recognition of the involvement of angiogenesis in major diseases hasbeen accompanied by research to identify and develop inhibitors ofangiogenesis. These inhibitors are generally classified in response todiscrete targets in the angiogenesis cascade, such as activation ofendothelial cells by an angiogenic signal; synthesis and release ofdegradative enzymes; endothelial cell migration; proliferation ofendothelial cells; and formation of capillary tubules. Therefore,angiogenesis occurs in many stages and attempts are underway to discoverand develop compounds that work to block angiogenesis at these variousstages.

There are publications that teach that inhibitors of angiogenesis,working by diverse mechanisms, are beneficial in diseases such as cancerand metastasis, ocular diseases, arthritis and hemangioma.

Vascular endothelial growth factor (VEGF), a polypeptide, is mitogenicfor endothelial cells in vitro and stimulates angiogenic responses invivo. VEGF has also been linked to inappropriate angiogenesis. VEGFR(s)are protein tyrosine kinases (PTKs). PTKs catalyze the phosphorylationof specific tyrosine residues in proteins involved in cell function thusregulating cell growth, survival and differentiation.

Three PTK receptors for VEGF have been identified: VEGFR-1 (Flt-1);VEGFR-2 (Flk-1 or KDR) and VEGFR-3 (Flt-4). These receptors are involvedin angiogenesis and participate in signal transduction. Of particularinterest is VEGFR-2, which is a transmembrane receptor PTK expressedprimarily in endothelial cells. Activation of VEGFR-2 by VEGF is acritical step in the signal transduction pathway that initiates tumourangiogenesis. VEGF expression may be constitutive to tumour cells andcan also be upregulated in response to certain stimuli. One such stimuliis hypoxia, where VEGF expression is upregulated in both tumour andassociated host tissues. The VEGF ligand activates VEGFR-2 by bindingwith its extracellular VEGF binding site. This leads to receptordimerization of VEGFRs and autophosphorylation of tyrosine residues atthe intracellular kinase domain of VEGFR-2. The kinase domain operatesto transfer a phosphate from ATP to the tyrosine residues, thusproviding binding sites for signalling proteins downstream of VEGFR-2leading ultimately to initiation of angiogenesis.

Inhibition at the kinase domain binding site of VEGFR-2 would blockphosphorylation of tyrosine residues and serve to disrupt initiation ofangiogenesis.

Angiogenesis is a physiologic process of new blood vessel formationmediated by various cytokines called angiogenic factors. Although itspotential pathophysiologic role in solid tumors has been extensivelystudied for more than 3 decades, enhancement of angiogenesis in chroniclymphocytic leukemia (CLL) and other malignant hematological disordershas been recognized more recently. An increased level of angiogenesishas been documented by various experimental methods both in bone marrowand lymph nodes of patients with CLL. Although the role of angiogenesisin the pathophysiology of this disease remains to be fully elucidated,experimental data suggest that several angiogenic factors play a role inthe disease progression. Biologic markers of angiogenesis were alsoshown to be of prognostic relevance in CLL. This indicates that VEGFRinhibitors may also be of benefit for patients with leukemia's such asCLL.

In order for a tumour mass to get beyond a critical size, it mustdevelop an associated vasculature. It has been proposed that targeting atumor vasculature would limit tumor expansion and could be a usefulcancer therapy. Observations of tumor growth have indicated that smalltumour masses can persist in a tissue without any tumour-specificvasculature. The growth arrest of nonvascularized tumors has beenattributed to the effects of hypoxia at the center of the tumor. Morerecently, a variety of proangiogenic and antiangiogenic factors havebeen identified and have led to the concept of the “angiogenic switch,”a process in which disruption of the normal ratio of angiogenic stimuliand inhibitors in a tumor mass allows for autonomous vascularization.The angiogenic switch appears to be governed by the same geneticalterations that drive malignant conversion: the activation of oncogenesand the loss of tumour suppressor genes. Several growth factors act aspositive regulators of angiogenesis. Foremost among these are vascularendothelial growth factor (VEGF), basic fibroblast growth factor (bFGF),and angiogenin. Proteins such as thrombospondin (Tsp-1), angiostatin,and endostatin function as negative regulators of angiogenesis.

Inhibition of VEGFR2 but not VEGFR1 markedly disrupts angiogenicswitching, persistent angiogenesis, and initial tumor growth in a mousemodel. In late-stage tumors, phenotypic resistance to VEGFR2 blockadeemerged, as tumors regrew during treatment after an initial period ofgrowth suppression. This resistance to VEGF blockade involvesreactivation of tumour angiogenesis, independent of VEGF and associatedwith hypoxia-mediated induction of other proangiogenic factors,including members of the FGF family. These other proangiogenic signalsare functionally implicated in the revascularization and regrowth oftumours in the evasion phase, as FGF blockade impairs progression in theface of VEGF inhibition.

There is evidence for normalization of glioblastoma blood vessels inpatients treated with a pan-VEGF receptor tyrosine kinase inhibitor,AZD2171, in a phase 2 study. MRI determination of vessel normalizationin combination with circulating biomarkers provides for an effectivemeans to assess response to antiangiogenic agents.

PDGFR

A malignant tumour is the product of uncontrolled cell proliferation.Cell growth is controlled by a delicate balance between growth-promotingand growth-inhibiting factors. In normal tissue the production andactivity of these factors results in differentiated cells growing in acontrolled and regulated manner that maintains the normal integrity andfunctioning of the organ. The malignant cell has evaded this control;the natural balance is disturbed (via a variety of mechanisms) andunregulated, aberrant cell growth occurs. A growth factor of importancein tumour development is the platelet-derived growth factor (PDGF) thatcomprises a family of peptide growth factors that signal through cellsurface tyrosine kinase receptors (PDGFR) and stimulate various cellularfunctions including growth, proliferation, and differentiation.

Advantages of a Selective Inhibitor

Development of FGFR kinase inhibitors with a differentiated selectivityprofile provides a new opportunity to use these targeted agents inpatient sub-groups whose disease is driven by FGFR deregulation.Compounds that exhibit reduced inhibitory action on additional kinases,particularly VEGFR2 and PDGFR-beta, offer the opportunity to have adifferentiated side-effect or toxicity profile and as such allow for amore effective treatment of these indications. Inhibitors of VEGFR2 andPDGFR-beta are associated with toxicities such as hypertension or oedemarespectively. In the case of VEGFR2 inhibitors this hypertensive effectis often dose limiting, may be contraindicated in certain patientpopulations and requires clinical management.

Biological Activity and Therapeutic Uses

The compounds of the invention, and subgroups thereof, have fibroblastgrowth factor receptor (FGFR) inhibiting or modulating activity and/orvascular endothelial growth factor receptor (VEGFR) inhibiting ormodulating activity, and/or platelet derived growth factor receptor(PDGFR) inhibiting or modulating activity, and which will be useful inpreventing or treating disease states or conditions described herein. Inaddition the compounds of the invention, and subgroups thereof, will beuseful in preventing or treating diseases or condition mediated by thekinases. References to the preventing or prophylaxis or treatment of adisease state or condition such as cancer include within their scopealleviating or reducing the incidence of cancer.

As used herein, the term “modulation”, as applied to the activity of akinase, is intended to define a change in the level of biologicalactivity of the protein kinase. Thus, modulation encompassesphysiological changes which effect an increase or decrease in therelevant protein kinase activity. In the latter case, the modulation maybe described as “inhibition”. The modulation may arise directly orindirectly, and may be mediated by any mechanism and at anyphysiological level, including for example at the level of geneexpression (including for example transcription, translation and/orpost-translational modification), at the level of expression of genesencoding regulatory elements which act directly or indirectly on thelevels of kinase activity. Thus, modulation may implyelevated/suppressed expression or over- or under-expression of a kinase,including gene amplification (i.e. multiple gene copies) and/orincreased or decreased expression by a transcriptional effect, as wellas hyper- (or hypo-)activity and (de)activation of the protein kinase(s)(including (de)activation) by mutation(s). The terms “modulated”,“modulating” and “modulate” are to be interpreted accordingly.

As used herein, the term “mediated”, as used e.g. in conjunction with akinase as described herein (and applied for example to variousphysiological processes, diseases, states, conditions, therapies,treatments or interventions) is intended to operate limitatively so thatthe various processes, diseases, states, conditions, treatments andinterventions to which the term is applied are those in which the kinaseplays a biological role. In cases where the term is applied to adisease, state or condition, the biological role played by a kinase maybe direct or indirect and may be necessary and/or sufficient for themanifestation of the symptoms of the disease, state or condition (or itsaetiology or progression). Thus, kinase activity (and in particularaberrant levels of kinase activity, e.g. kinase over-expression) neednot necessarily be the proximal cause of the disease, state orcondition: rather, it is contemplated that the kinase mediated diseases,states or conditions include those having multifactoral aetiologies andcomplex progressions in which the kinase in question is only partiallyinvolved. In cases where the term is applied to treatment, prophylaxisor intervention, the role played by the kinase may be direct or indirectand may be necessary and/or sufficient for the operation of thetreatment, prophylaxis or outcome of the intervention. Thus, a diseasestate or condition mediated by a kinase includes the development ofresistance to any particular cancer drug or treatment.

Thus, for example, the compounds of the invention may be useful inalleviating or reducing the incidence of cancer.

More particularly, the compounds of the formulae (I) and sub-groupsthereof are inhibitors of FGFRs. For example, compounds of the inventionhave activity against FGFR1, FGFR2, FGFR3, and/or FGFR4, and inparticular FGFRs selected from FGFR1, FGFR2 and FGFR3; or in particularthe compounds of formula (I) and sub-groups thereof are inhibitors ofFGFR4.

Preferred compounds are compounds that inhibit one or more FGFR selectedfrom FGFR1, FGFR2, FGFR3, and FGFR4. Preferred compounds of theinvention are those having IC₅₀ values of less than 0.1 μM.

Compounds of the invention also have activity against VEGFR.

In addition many of the compounds of the invention exhibit selectivityfor the FGFR 1, 2, and/or 3, and/or 4 compared to VEGFR (in particularVEGFR2) and/or PDGFR and such compounds represent one preferredembodiment of the invention. In particular, the compounds exhibitselectivity over VEGFR2. For example, many compounds of the inventionhave IC₅₀ values against FGFR1, 2 and/or 3 and/or 4 that are between atenth and a hundredth of the IC₅₀ against VEGFR (in particular VEGFR2)and/or PDGFR B. In particular preferred compounds of the invention haveat least 10 times greater activity against or inhibition of FGFR inparticular FGFR1, FGFR2, FGFR3 and/or FGFR4 than VEGFR2. More preferablythe compounds of the invention have at least 100 times greater activityagainst or inhibition of FGFR in particular FGFR1, FGFR2, FGFR3 and/orFGFR4 than VEGFR2. This can be determined using the methods describedherein.

As a consequence of their activity in modulating or inhibiting FGFR,and/or VEGFR kinases, the compounds will be useful in providing a meansof preventing the growth or inducing apoptosis of neoplasias,particularly by inhibiting angiogenesis. It is therefore anticipatedthat the compounds will prove useful in treating or preventingproliferative disorders such as cancers. In addition, the compounds ofthe invention could be useful in the treatment of diseases in whichthere is a disorder of proliferation, apoptosis or differentiation.

In particular tumours with activating mutants of VEGFR or upregulationof VEGFR and patients with elevated levels of serum lactatedehydrogenase may be particularly sensitive to the compounds of theinvention. Patients with activating mutants of any of the isoforms ofthe specific RTKs discussed herein may also find treatment with thecompounds of the invention particularly beneficial. For example, VEGFRoverexpression in acute leukemia cells where the clonal progenitor mayexpress VEGFR. Also, particular tumours with activating mutants orupregulation or overexpression of any of the isoforms of FGFR such asFGFR1, FGFR2 or FGFR3 or FGFR4 may be particularly sensitive to thecompounds of the invention and thus patients as discussed herein withsuch particular tumours may also find treatment with the compounds ofthe invention particularly beneficial. It may be preferred that thetreatment is related to or directed at a mutated form of one of thereceptor tyrosine kinases, such as discussed herein. Diagnosis oftumours with such mutations could be performed using techniques known toa person skilled in the art and as described herein such as RTPCR andFISH.

Examples of cancers which may be treated (or inhibited) include, but arenot limited to, a carcinoma, for example a carcinoma of the bladder,breast, colon (e.g. colorectal carcinomas such as colon adenocarcinomaand colon adenoma), kidney, urothelial, uterus, epidermis, liver, lung(for example adenocarcinoma, small cell lung cancer and non-small celllung carcinomas, squamous lung cancer), oesophagus, head and neck, gallbladder, ovary, pancreas (e.g. exocrine pancreatic carcinoma), stomach,gastrointestinal (also known as gastric) cancer (e.g. gastrointestinalstromal tumours), cervix, endometrium, thyroid, prostate, or skin (forexample squamous cell carcinoma or dermatofibrosarcoma protuberans);pituitary cancer, a hematopoietic tumour of lymphoid lineage, forexample leukemia, acute lymphocytic leukemia, chronic lymphocyticleukemia, B-cell lymphoma (e.g. diffuse large B-cell lymphoma), T-celllymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, hairy celllymphoma, or Burkett's lymphoma; a hematopoietic tumour of myeloidlineage, for example leukemias, acute and chronic myelogenous leukemias,chronic myelomonocytic leukemia (CMML), myeloproliferative disorder,myeloproliferative syndrome, myelodysplastic syndrome, or promyelocyticleukemia; multiple myeloma; thyroid follicular cancer; hepatocellularcancer, a tumour of mesenchymal origin (e.g. Ewing's sarcoma), forexample fibrosarcoma or rhabdomyosarcoma; a tumour of the central orperipheral nervous system, for example astrocytoma, neuroblastoma,glioma (such as glioblastoma multiforme) or schwannoma; melanoma;seminoma; teratocarcinoma; osteosarcoma; xeroderma pigmentosum;keratoctanthoma; thyroid follicular cancer; or Kaposi's sarcoma. Inparticular, squamous lung cancer, breast cancer, colorectal cancer,glioblastoma, astrocytomas, prostate cancer, small cell lung cancer,melanoma, head and neck cancer, thyroid cancer, uterine cancer, gastriccancer, hepatocellular cancer, cervix cancer, multiple myeloma, bladdercancer, endometrial cancer, urothelial cancer, colon cancer,rhabdomyosarcoma, pituitary gland cancer.

Certain cancers are resistant to treatment with particular drugs. Thiscan be due to the type of the tumour or can arise due to treatment withthe compound. In this regard, references to multiple myeloma includesbortezomib sensitive multiple myeloma or refractory multiple myeloma.Similarly, references to chronic myelogenous leukemia includes imitanibsensitive chronic myelogenous leukemia and refractory chronicmyelogenous leukemia. Chronic myelogenous leukemia is also known aschronic myeloid leukemia, chronic granulocytic leukemia or CML.Likewise, acute myelogenous leukemia, is also called acute myeloblasticleukemia, acute granulocytic leukemia, acute nonlymphocytic leukaemia orAML.

The compounds of the invention can also be used in the treatment ofhematopoetic diseases of abnormal cell proliferation whetherpre-malignant or stable such as myeloproliferative diseases.Myeloproliferative diseases (“MPD”s) are a group of diseases of the bonemarrow in which excess cells are produced. They are related to, and mayevolve into, myelodysplastic syndrome. Myeloproliferative diseasesinclude polycythemia vera, essential thrombocythemia and primarymyelofibrosis. A further haematological disorder is hypereosinophilicsyndrome. T-cell lymphoproliferative diseases include those derived fromnatural Killer cells.

In addition the compounds of the invention can be used togastrointestinal (also known as gastric) cancer e.g. gastrointestinalstromal tumours. Gastrointestinal cancer refers to malignant conditionsof the gastrointestinal tract, including the esophagus, stomach, liver,biliary system, pancreas, bowels, and anus.

Thus, in the pharmaceutical compositions, uses or methods of thisinvention for treating a disease or condition comprising abnormal cellgrowth, the disease or condition comprising abnormal cell growth in oneembodiment is a cancer.

Particular subsets of cancers include multiple myeloma, bladder,cervical, prostate and thyroid carcinomas, lung, breast, and coloncancers.

A further subset of cancers includes multiple myeloma, bladder,hepatocellular, oral squamous cell carcinoma and cervical carcinomas.

The compound of the invention, having FGFR such as FGFR1 inhibitoryactivity, may be particularly useful in the treatment or prevention ofbreast cancer in particular Classic Lobular Carcinomas (CLC).

As the compounds of the invention have FGFR4 activity they will also beuseful in the treatment of prostate or pituitary cancers, or they willbe useful in the treatment of breast cancer, lung cancer, prostatecancer, liver cancer (HCC) or lung cancer.

In particular the compounds of the invention as FGFR inhibitors, areuseful in the treatment of multiple myeloma, myeloproliferatoivedisorders, endometrial cancer, prostate cancer, bladder cancer, lungcancer, ovarian cancer, breast cancer, gastric cancer, colorectalcancer, and oral squamous cell carcinoma.

Further subsets of cancer are multiple myeloma, endometrial cancer,bladder cancer, cervical cancer, prostate cancer, lung cancer, breastcancer, colorectal cancer and thyroid carcinomas.

In particular the compounds of the invention are useful in the treatmentof multiple myeloma (in particular multiple myeloma with t(4; 14)translocation or overexpressing FGFR3), prostate cancer (hormonerefractory prostrate carcinomas), endometrial cancer (in particularendometrial tumours with activating mutations in FGFR2) and breastcancer (in particular lobular breast cancer).

In particular the compounds are useful in the treatment of lobularcarcinomas such as CLC (Classic lobular carcinoma).

As the compounds have activity against FGFR3 they will be useful in thetreatment of multiple myeloma and bladder cancer.

In particular the compounds are useful for the treatment of t(4;14)translocation positive multiple myeloma.

In one embodiment the compounds may be useful for the treatment ofsarcoma. In one embodiment the compounds may be useful for the treatmentof lung cancer, e.g. squamous cell carcinoma.

As the compounds have activity against FGFR2 they will be useful in thetreatment of endometrial, ovarian, gastric, hepatocellular, uterine,cervix and colorectal cancers.

FGFR2 is also overexpressed in epithelial ovarian cancer, therefore thecompounds of the invention may be specifically useful in treatingovarian cancer such as epithelial ovarian cancer.

In one embodiment, the compounds may be useful for the treatment of lungcancer, in particular NSCLC, squamous cell carcinoma, liver cancer,kidney cancer, breast cancer, colon cancer, colorectal cancer, prostatecancer.

In one embodiment, the compounds may be useful for the treatment ofprostate cancer, bladder cancer, lung cancer such as NSCLC, breastcancer, gastric cancer, and liver cancer (HCC (hepatocellular cancer)).

Compounds of the invention may also be useful in the treatment oftumours pre-treated with VEGFR2 inhibitor or VEGFR2 antibody (e.g.Avastin).

In particular the compounds of the invention may be useful in thetreatment of VEGFR2-resistant tumours. VEGFR2 inhibitors and antibodiesare used in the treatment of thyroid and renal cell carcinomas,therefore the compounds of the invention may be useful in the treatmentof VEGFR2-resistant thyroid and renal cell carcinomas.

The cancers may be cancers which are sensitive to inhibition of any oneor more FGFRs selected from FGFR1, FGFR2, FGFR3, FGFR4, for example, oneor more FGFRs selected from FGFR1, FGFR2 or FGFR3.

Whether or not a particular cancer is one which is sensitive toinhibition of FGFR or VEGFR signalling may be determined by means of acell growth assay as set out below or by a method as set out in thesection headed “Methods of Diagnosis”.

The compounds of the invention, and in particular those compounds havingFGFR, or VEGFR inhibitory activity, may be particularly useful in thetreatment or prevention of cancers of a type associated with orcharacterised by the presence of elevated levels of FGFR, or VEGFR, forexample the cancers referred to in this context in the introductorysection of this application.

The compounds of the present invention may be useful for the treatmentof the adult population. The compounds of the present invention may beuseful for the treatment of the pediatric population.

It has been discovered that some FGFR inhibitors can be used incombination with other anticancer agents. For example, it may bebeneficial to combine an inhibitor that induces apoptosis with anotheragent which acts via a different mechanism to regulate cell growth thustreating two of the characteristic features of cancer development.Examples of such combinations are set out below.

The compounds of the invention may be useful in treating otherconditions which result from disorders in proliferation such as type IIor non-insulin dependent diabetes mellitus, autoimmune diseases, headtrauma, stroke, epilepsy, neurodegenerative diseases such asAlzheimer's, motor neurone disease, progressive supranuclear palsy,corticobasal degeneration and Pick's disease for example autoimmunediseases and neurodegenerative diseases.

One sub-group of disease states and conditions that the compounds of theinvention may be useful consists of inflammatory diseases,cardiovascular diseases and wound healing.

FGFR, and VEGFR are also known to play a role in apoptosis,angiogenesis, proliferation, differentiation and transcription andtherefore the compounds of the invention could also be useful in thetreatment of the following diseases other than cancer; chronicinflammatory diseases, for example systemic lupus erythematosus,autoimmune mediated glomerulonephritis, rheumatoid arthritis, psoriasis,inflammatory bowel disease, autoimmune diabetes mellitus, Eczemahypersensitivity reactions, asthma, COPD, rhinitis, and upperrespiratory tract disease; cardiovascular diseases for example cardiachypertrophy, restenosis, atherosclerosis; neurodegenerative disorders,for example Alzheimer's disease, AIDS-related dementia, Parkinson'sdisease, amyotropic lateral sclerosis, retinitis pigmentosa, spinalmuscular atropy and cerebellar degeneration; glomerulonephritis;myelodysplastic syndromes, ischemic injury associated myocardialinfarctions, stroke and reperfusion injury, arrhythmia, atherosclerosis,toxin-induced or alcohol related liver diseases, haematologicaldiseases, for example, chronic anemia and aplastic anemia; degenerativediseases of the musculoskeletal system, for example, osteoporosis andarthritis, aspirin-sensitive rhinosinusitis, cystic fibrosis, multiplesclerosis, kidney diseases and cancer pain.

In addition, mutations of FGFR2 are associated with several severeabnormalities in human skeletal development and thus the compounds ofinvention could be useful in the treatment of abnormalities in humanskeletal development, including abnormal ossification of cranial sutures(craniosynostosis), Apert (AP) syndrome, Crouzon syndrome, Jackson-Weisssyndrome, Beare-Stevenson cutis gyrate syndrome, and Pfeiffer syndrome.

The compound of the invention, having FGFR such as FGFR2 or FGFR3inhibitory activity, may be particularly useful in the treatment orprevention of the skeletal diseases. Particular skeletal diseases areachondroplasia or thanatophoric dwarfism (also known as thanatophoricdysplasia).

The compound of the invention, having FGFR such as FGFR1, FGFR2 or FGFR3inhibitory activity, may be particularly useful in the treatment orprevention in pathologies in which progressive fibrosis is a symptom.Fibrotic conditions in which the compounds of the inventions may beuseful in the treatment of include diseases exhibiting abnormal orexcessive deposition of fibrous tissue for example in liver cirrhosis,glomerulonephritis, pulmonary fibrosis, systemic fibrosis, rheumatoidarthritis, as well as the natural process of wound healing. Inparticular the compounds of the inventions may also be useful in thetreatment of lung fibrosis in particular in idiopathic pulmonaryfibrosis.

The over-expression and activation of FGFR and VEGFR in tumor-associatedvasculature has also suggested a role for compounds of the invention inpreventing and disrupting initiation of tumor angiogenesis. Inparticular the compounds of the invention may be useful in the treatmentof cancer, metastasis, leukemia's such as CLL, ocular diseases such asage-related macular degeneration in particular wet form of age-relatedmacular degeneration, ischemic proliferative retinopathies such asretinopathy of prematurity (ROP) and diabetic retinopathy, rheumatoidarthritis and hemangioma.

The activity of the compounds of the invention as inhibitors of FGFR1-4,VEGFR and/or PDGFR A/B can be measured using the assays set forth in theexamples below and the level of activity exhibited by a given compoundcan be defined in terms of the IC₅₀ value. Preferred compounds of thepresent invention are compounds having an IC₅₀ value of less than 1 μM,more preferably less than 0.1 μM.

The invention provides compounds that have FGFR inhibiting or modulatingactivity, and which may be useful in preventing or treating diseasestates or conditions mediated by FGFR kinases.

In one embodiment, there is provided a compound as defined herein foruse in therapy, for use as a medicine. In a further embodiment, there isprovided a compound as defined herein for use in the prophylaxis ortreatment, in particular in the treatment, of a disease state orcondition mediated by a FGFR kinase.

Thus, for example, the compounds of the invention may be useful inalleviating or reducing the incidence of cancer. Therefore, in a furtherembodiment, there is provided a compound as defined herein for use inthe prophylaxis or treatment, in particular the treatment, of cancer. Inone embodiment, the compound as defined herein is for use in theprophylaxis or treatment of FGFR-dependent cancer. In one embodiment,the compound as defined herein is for use in the prophylaxis ortreatment of cancer mediated by FGFR kinases.

Accordingly, the invention provides inter alia:

-   -   A method for the prophylaxis or treatment of a disease state or        condition mediated by a FGFR kinase, which method comprises        administering to a subject in need thereof a compound of the        formula (I) as defined herein.    -   A method for the prophylaxis or treatment of a disease state or        condition as described herein, which method comprises        administering to a subject in need thereof a compound of the        formula (I) as defined herein.    -   A method for the prophylaxis or treatment of cancer, which        method comprises administering to a subject in need thereof a        compound of the formula (I) as defined herein.    -   A method for alleviating or reducing the incidence of a disease        state or condition mediated by a FGFR kinase, which method        comprises administering to a subject in need thereof a compound        of the formula (I) as defined herein.    -   A method of inhibiting a FGFR kinase, which method comprises        contacting the kinase with a kinase-inhibiting compound of the        formula (I) as defined herein.    -   A method of modulating a cellular process (for example cell        division) by inhibiting the activity of a FGFR kinase using a        compound of the formula (I) as defined herein.    -   A compound of formula (I) as defined herein for use as a        modulator of a cellular process (for example cell division) by        inhibiting the activity of a FGFR kinase.    -   A compound of formula (I) as defined herein for use in the        prophylaxis or treatment of cancer, in particular the treatment        of cancer.    -   A compound of formula (I) as defined herein for use as a        modulator (e.g. inhibitor) of FGFR.    -   The use of a compound of formula (I) as defined herein for the        manufacture of a medicament for the prophylaxis or treatment of        a disease state or condition mediated by a FGFR kinase, the        compound having the formula (I) as defined herein.    -   The use of a compound of formula (I) as defined herein for the        manufacture of a medicament for the prophylaxis or treatment of        a disease state or condition as described herein.    -   The use of a compound of formula (I) as defined herein for the        manufacture of a medicament for the prophylaxis or treatment, in        particular the treatment, of cancer.    -   The use of a compound of formula (I) as defined herein for the        manufacture of a medicament for modulating (e.g. inhibiting) the        activity of FGFR.    -   Use of a compound of formula (I) as defined herein in the        manufacture of a medicament for modulating a cellular process        (for example cell division) by inhibiting the activity of a FGFR        kinase.    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for prophylaxis or treatment of        a disease or condition characterised by up-regulation of a FGFR        kinase (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4).    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of a cancer, the cancer being one which is characterised by        up-regulation of a FGFR kinase (e.g. FGFR1 or FGFR2 or FGFR3 or        FGFR4).    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of cancer in a patient selected from a sub-population possessing        a genetic aberrations of FGFR3 kinase.    -   The use of a compound of the formula (I) as defined herein for        the manufacture of a medicament for the prophylaxis or treatment        of cancer in a patient who has been diagnosed as forming part of        a sub-population possessing a genetic aberrations of FGFR3        kinase.    -   A method for the prophylaxis or treatment of a disease or        condition characterised by up-regulation of a FGFR kinase (e.g.        FGFR1 or FGFR2 or FGFR3 or FGFR4), the method comprising        administering a compound of the formula (I) as defined herein.    -   A method for alleviating or reducing the incidence of a disease        or condition characterised by up-regulation of a FGFR kinase        (e.g. FGFR1 or FGFR2 or FGFR3 or FGFR4), the method comprising        administering a compound of the formula (I) as defined herein.    -   A method for the prophylaxis or treatment of (or alleviating or        reducing the incidence of) cancer in a patient suffering from or        suspected of suffering from cancer; which method comprises (i)        subjecting a patient to a diagnostic test to determine whether        the patient possesses a genetic aberrations of FGFR3 gene;        and (ii) where the patient does possess the said variant,        thereafter administering to the patient a compound of the        formula (I) as defined herein having FGFR3 kinase inhibiting        activity.    -   A method for the prophylaxis or treatment of (or alleviating or        reducing the incidence of) a disease state or condition        characterised by up-regulation of an FGFR kinase (e.g. FGFR1 or        FGFR2 or FGFR3 or FGFR4); which method comprises (i) subjecting        a patient to a diagnostic test to detect a marker characteristic        of up-regulation of a FGFR kinase (e.g. FGFR1 or FGFR2 or FGFR3        or FGFR4) and (ii) where the diagnostic test is indicative of        up-regulation of a FGFR kinase, thereafter administering to the        patient a compound of the formula (I) as defined herein having        FGFR kinase inhibiting activity.

In one embodiment, the disease mediated by FGFR kinases is a oncologyrelated disease (e.g. cancer). In one embodiment, the disease mediatedby FGFR kinases is a non-oncology related disease (e.g. any diseasedisclosed herein excluding cancer). In one embodiment the diseasemediated by FGFR kinases is a condition described herein. In oneembodiment the disease mediated by FGFR kinases is a skeletal conditiondescribed herein. Particular abnormalities in human skeletaldevelopment, include abnormal ossification of cranial sutures(craniosynostosis), Apert (AP) syndrome, Crouzon syndrome, Jackson-Weisssyndrome, Beare-Stevenson cutis gyrate syndrome, Pfeiffer syndrome,achondroplasia and thanatophoric dwarfism (also known as thanatophoricdysplasia).

Mutated Kinases

Drug resistant kinase mutations can arise in patient populations treatedwith kinase inhibitors. These occur, in part, in the regions of theprotein that bind to or interact with the particular inhibitor used intherapy. Such mutations reduce or increase the capacity of the inhibitorto bind to and inhibit the kinase in question. This can occur at any ofthe amino acid residues which interact with the inhibitor or areimportant for supporting the binding of said inhibitor to the target. Aninhibitor that binds to a target kinase without requiring theinteraction with the mutated amino acid residue will likely beunaffected by the mutation and will remain an effective inhibitor of theenzyme.

A study in gastric cancer patient samples showed the presence of twomutations in FGFR2, Ser167Pro in exon IIIa and a splice site mutation940-2A-G in exon IIIc. These mutations are identical to the germlineactivating mutations that cause craniosynotosis syndromes and wereobserved in 13% of primary gastric cancer tissues studied. In additionactivating mutations in FGFR3 were observed in 5% of the patient samplestested and overexpression of FGFRs has been correlated with a poorprognosis in this patient group.

In addition there are chromosomal translocations or point mutations thathave been observed in FGFR which give rise to gain-of-function,over-expressed, or constitutively active biological states.

The compounds of the invention would therefore find particularapplication in relation to cancers which express a mutated moleculartarget such as FGFR. Diagnosis of tumours with such mutations could beperformed using techniques known to a person skilled in the art and asdescribed herein such as RTPCR and FISH.

It has been suggested that mutations of a conserved threonine residue atthe ATP binding site of FGFR would result in inhibitor resistance. Theamino acid valine 561 has been mutated to a methionine in FGFR1 whichcorresponds to previously reported mutations found in Abl (T315) andEGFR (T766) that have been shown to confer resistance to selectiveinhibitors. Assay data for FGFR1 V561M showed that this mutationconferred resistance to a tyrosine kinase inhibitor compared to that ofthe wild type.

Methods of Diagnosis

Prior to administration of a compound of the formula (I), a patient maybe screened to determine whether a disease or condition from which thepatient is or may be suffering is one which would be susceptible totreatment with a compound having activity against FGFR, and/or VEGFR.

For example, a biological sample taken from a patient may be analysed todetermine whether a condition or disease, such as cancer, that thepatient is or may be suffering from is one which is characterised by agenetic abnormality or abnormal protein expression which leads toup-regulation of the levels or activity of FGFR, and/or VEGFR or tosensitisation of a pathway to normal FGFR, and/or VEGFR activity, or toupregulation of these growth factor signalling pathways such as growthfactor ligand levels or growth factor ligand activity or to upregulationof a biochemical pathway downstream of FGFR, and/or VEGFR activation.

Examples of such abnormalities that result in activation orsensitisation of the FGFR, and/or VEGFR signal include loss of, orinhibition of apoptotic pathways, up-regulation of the receptors orligands, or presence of mutant variants of the receptors or ligands e.gPTK variants. Tumours with mutants of FGFR1, FGFR2 or FGFR3 or FGFR4 orup-regulation, in particular over-expression of FGFR1, orgain-of-function mutants of FGFR2 or FGFR3 may be particularly sensitiveto FGFR inhibitors.

For example, point mutations engendering gain-of-function in FGFR2 havebeen identified in a number of conditions. In particular activatingmutations in FGFR2 have been identified in 10% of endometrial tumours.

In addition, genetic aberrations of the FGFR3 receptor tyrosine kinasesuch as chromosomal translocations or point mutations resulting inectopically expressed or deregulated, constitutively active, FGFR3receptors have been identified and are linked to a subset of multiplemyelomas, bladder and cervical carcinomas. A particular mutation T674Iof the PDGF receptor has been identified in imatinib-treated patients.In addition, a gene amplification of 8p12-p11.2 was demonstrated in 50%of lobular breast cancer (CLC) cases and this was shown to be linkedwith an increased expression of FGFR1. Preliminary studies with siRNAdirected against FGFR1, or a small molecule inhibitor of the receptor,showed cell lines harbouring this amplification to be particularlysensitive to inhibition of this signalling pathway.

Alternatively, a biological sample taken from a patient may be analysedfor loss of a negative regulator or suppressor of FGFR or VEGFR. In thepresent context, the term “loss” embraces the deletion of a geneencoding the regulator or suppressor, the truncation of the gene (forexample by mutation), the truncation of the transcribed product of thegene, or the inactivation of the transcribed product (e.g. by pointmutation) or sequestration by another gene product.

The term up-regulation includes elevated expression or over-expression,including gene amplification (i.e. multiple gene copies) and increasedexpression by a transcriptional effect, and hyperactivity andactivation, including activation by mutations. Thus, the patient may besubjected to a diagnostic test to detect a marker characteristic ofup-regulation of FGFR, and/or VEGFR. The term diagnosis includesscreening. By marker we include genetic markers including, for example,the measurement of DNA composition to identify mutations of FGFR, and/orVEGFR. The term marker also includes markers which are characteristic ofup regulation of FGFR and/or VEGFR, including enzyme activity, enzymelevels, enzyme state (e.g. phosphorylated or not) and mRNA levels of theaforementioned proteins.

The diagnostic tests and screens are typically conducted on a biologicalsample selected from tumour biopsy samples, blood samples (isolation andenrichment of shed tumour cells), stool biopsies, sputum, chromosomeanalysis, pleural fluid, peritoneal fluid, buccal spears, biopsy orurine.

Methods of identification and analysis of mutations and up-regulation ofproteins are known to a person skilled in the art. Screening methodscould include, but are not limited to, standard methods such asreverse-transcriptase polymerase chain reaction (RT-PCR) or in-situhybridization such as fluorescence in situ hybridization (FISH).

Identification of an individual carrying a mutation in FGFR, and/orVEGFR may mean that the patient would be particularly suitable fortreatment with a FGFR, and/or VEGFR inhibitor. Tumours maypreferentially be screened for presence of a FGFR, and for VEGFR variantprior to treatment. The screening process will typically involve directsequencing, oligonucleotide microarray analysis, or a mutant specificantibody. In addition, diagnosis of tumours with such mutations could beperformed using techniques known to a person skilled in the art and asdescribed herein such as RT-PCR and FISH.

In addition, mutant forms of, for example FGFR or VEGFR2, can beidentified by direct sequencing of, for example, tumour biopsies usingPCR and methods to sequence PCR products directly as hereinbeforedescribed. The skilled artisan will recognize that all such well-knowntechniques for detection of the over expression, activation or mutationsof the aforementioned proteins could be applicable in the present case.

In screening by RT-PCR, the level of mRNA in the tumour is assessed bycreating a cDNA copy of the mRNA followed by amplification of the cDNAby PCR. Methods of PCR amplification, the selection of primers, andconditions for amplification, are known to a person skilled in the art.Nucleic acid manipulations and PCR are carried out by standard methods,as described for example in Ausubel, F. M. et al., eds. (2004) CurrentProtocols in Molecular Biology, John Wiley & Sons Inc., or Innis, M. A.et al., eds. (1990) PCR Protocols: a guide to methods and applications,Academic Press, San Diego. Reactions and manipulations involving nucleicacid techniques are also described in Sambrook et al., (2001), 3^(rd)Ed, Molecular Cloning: A Laboratory Manual, Cold Spring HarborLaboratory Press. Alternatively a commercially available kit for RT-PCR(for example Roche Molecular Biochemicals) may be used, or methodologyas set forth in U.S. Pat. Nos. 4,666,828; 4,683,202; 4,801,531;5,192,659, 5,272,057, 5,882,864, and 6,218,529 and incorporated hereinby reference. An example of an in-situ hybridisation technique forassessing mRNA expression would be fluorescence in-situ hybridisation(FISH) (see Angerer (1987) Meth. Enzymol., 152: 649).

Generally, in situ hybridization comprises the following major steps:(1) fixation of tissue to be analyzed; (2) prehybridization treatment ofthe sample to increase accessibility of target nucleic acid, and toreduce nonspecific binding; (3) hybridization of the mixture of nucleicacids to the nucleic acid in the biological structure or tissue; (4)post-hybridization washes to remove nucleic acid fragments not bound inthe hybridization, and (5) detection of the hybridized nucleic acidfragments. The probes used in such applications are typically labelled,for example, with radioisotopes or fluorescent reporters. Preferredprobes are sufficiently long, for example, from about 50, 100, or 200nucleotides to about 1000 or more nucleotides, to enable specifichybridization with the target nucleic acid(s) under stringentconditions. Standard methods for carrying out FISH are described inAusubel, F. M. et al., eds. (2004) Current Protocols in MolecularBiology, John Wiley & Sons Inc and Fluorescence In Situ Hybridization:Technical Overview by John M. S. Bartlett in Molecular Diagnosis ofCancer, Methods and Protocols, 2nd ed.; ISBN: 1-59259-760-2; March 2004,pps. 077-088; Series: Methods in Molecular Medicine.

Methods for gene expression profiling are described by (DePrimo et al.(2003), BMC Cancer, 3:3). Briefly, the protocol is as follows:double-stranded cDNA is synthesized from total RNA Using a (dT)24oligomer for priming first-strand cDNA synthesis, followed by secondstrand cDNA synthesis with random hexamer primers. The double-strandedcDNA is used as a template for in vitro transcription of cRNA usingbiotinylated ribonucleotides. cRNA is chemically fragmented according toprotocols described by Affymetrix (Santa Clara, Calif., USA), and thenhybridized overnight on Human Genome Arrays.

Alternatively, the protein products expressed from the mRNAs may beassayed by immunohistochemistry of tumour samples, solid phaseimmunoassay with microtitre plates, Western blotting, 2-dimensionalSDS-polyacrylamide gel electrophoresis, ELISA, flow cytometry and othermethods known in the art for detection of specific proteins. Detectionmethods would include the use of site specific antibodies. The skilledperson will recognize that all such well-known techniques for detectionof upregulation of FGFR, and/or VEGFR, or detection of FGFR, and/orVEGFR variants or mutants could be applicable in the present case.

Abnormal levels of proteins such as FGFR or VEGFR can be measured usingstandard enzyme assays, for example, those assays described herein.Activation or overexpression could also be detected in a tissue sample,for example, a tumour tissue. By measuring the tyrosine kinase activitywith an assay such as that from Chemicon International. The tyrosinekinase of interest would be immunoprecipitated from the sample lysateand its activity measured.

Alternative methods for the measurement of the over expression oractivation of FGFR or VEGFR including the isoforms thereof, include themeasurement of microvessel density. This can for example be measuredusing methods described by Orre and Rogers (Int J Cancer (1999), 84(2)101-8). Assay methods also include the use of markers, for example, inthe case of VEGFR these include CD31, CD34 and CD105.

Therefore all of these techniques could also be used to identify tumoursparticularly suitable for treatment with the compounds of the invention.

The compounds of the invention are particular useful in treatment of apatient having a mutated FGFR. The G697C mutation in FGFR3 is observedin 62% of oral squamous cell carcinomas and causes constitutiveactivation of the kinase activity. Activating mutations of FGFR3 havealso been identified in bladder carcinoma cases. These mutations were of6 kinds with varying degrees of prevelence: R248C, S249C, G372C, S373C,Y375C, K652Q. In addition, a Gly388Arg polymorphism in FGFR4 has beenfound to be associated with increased incidence and aggressiveness ofprostate, colon, lung, liver (HCC) and breast cancer.

Therefore in a further aspect the invention includes use of a compoundaccording to the invention for the manufacture of a medicament for thetreatment or prophylaxis of a disease state or condition in a patientwho has been screened and has been determined as suffering from, orbeing at risk of suffering from, a disease or condition which would besusceptible to treatment with a compound having activity against FGFR.

Particular mutations a patient is screened for include G697C, R248C,S249C, G372C, S373C, Y375C, K652Q mutations in FGFR3 and Gly388Argpolymorphism in FGFR4.

In another aspect the invention includes a compound of the invention foruse in the prophylaxis or treatment of cancer in a patient selected froma sub-population possessing a variant of the FGFR gene (for exampleG697C mutation in FGFR3 and Gly388Arg polymorphism in FGFR4).

MRI determination of vessel normalization (e.g. using MRI gradient echo,spin echo, and contrast enhancement to measure blood volume, relativevessel size, and vascular permeability) in combination with circulatingbiomarkers (circulating progenitor cells (CPCs), CECs, SDF1, and FGF2)may also be used to identify VEGFR2-resistant tumours for treatment witha compound of the invention.

Pharmaceutical Compositions and Combinations

In view of their useful pharmacological properties, the subjectcompounds may be formulated into various pharmaceutical forms foradministration purposes.

In one embodiment the pharmaceutical composition (e.g. formulation)comprises at least one active compound of the invention together withone or more pharmaceutically acceptable carriers, adjuvants, excipients,diluents, fillers, buffers, stabilisers, preservatives, lubricants, orother materials well known to those skilled in the art and optionallyother therapeutic or prophylactic agents.

To prepare the pharmaceutical compositions of this invention, aneffective amount of a compound of the present invention, as the activeingredient is combined in intimate admixture with a pharmaceuticallyacceptable carrier, which carrier may take a wide variety of formsdepending on the form of preparation desired for administration. Thepharmaceutical compositions can be in any form suitable for oral,parenteral, topical, intranasal, ophthalmic, otic, rectal,intra-vaginal, or transdermal administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, rectally, percutaneously, or by parenteralinjection. For example, in preparing the compositions in oral dosageform, any of the usual pharmaceutical media may be employed, such as,for example, water, glycols, oils, alcohols and the like in the case oforal liquid preparations such as suspensions, syrups, elixirs andsolutions; or solid carriers such as starches, sugars, kaolin,lubricants, binders, disintegrating agents and the like in the case ofpowders, pills, capsules and tablets.

Because of their ease in administration, tablets and capsules representthe most advantageous oral dosage unit form, in which case solidpharmaceutical carriers are obviously employed. For parenteralcompositions, the carrier will usually comprise sterile water, at leastin large part, though other ingredients, to aid solubility for example,may be included. Injectable solutions, for example, may be prepared inwhich the carrier comprises saline solution, glucose solution or amixture of saline and glucose solution. Injectable suspensions may alsobe prepared in which case appropriate liquid carriers, suspending agentsand the like may be employed. In the compositions suitable forpercutaneous administration, the carrier optionally comprises apenetration enhancing agent and/or a suitable wetting agent, optionallycombined with suitable additives of any nature in minor proportions,which additives do not cause a significant deleterious effect to theskin. Said additives may facilitate the administration to the skinand/or may be helpful for preparing the desired compositions. Thesecompositions may be administered in various ways, e.g., as a transdermalpatch, as a spot-on, as an ointment. It is especially advantageous toformulate the aforementioned pharmaceutical compositions in dosage unitform for ease of administration and uniformity of dosage. Dosage unitform as used in the specification and claims herein refers to physicallydiscrete units suitable as unitary dosages, each unit containing apredetermined quantity of active ingredient calculated to produce thedesired therapeutic effect in association with the requiredpharmaceutical carrier. Examples of such dosage unit forms are tablets(including scored or coated tablets), capsules, pills, powder packets,wafers, injectable solutions or suspensions, teaspoonfuls,tablespoonfuls and the like, and segregated multiples thereof.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient, calculated to produce the desiredtherapeutic effect, in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The compound of the invention is administered in an amount sufficient toexert its anti-tumour activity.

Those skilled in the art could easily determine the effective amountfrom the test results presented hereinafter. In general it iscontemplated that a therapeutically effective amount would be from 0.005mg/kg to 100 mg/kg body weight, and in particular from 0.005 mg/kg to 10mg/kg body weight. It may be appropriate to administer the required doseas single, two, three, four or more sub-doses at appropriate intervalsthroughout the day. Said sub-doses may be formulated as unit dosageforms, for example, containing 0.5 to 500 mg, in particular 1 mg to 500mg, more in particular 10 mg to 500 mg of active ingredient per unitdosage form.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% by weight, more preferablyfrom 0.1 to 70% by weight, even more preferably from 0.1 to 50% byweight of the compound of the present invention, and, from 1 to 99.95%by weight, more preferably from 30 to 99.9% by weight, even morepreferably from 50 to 99.9% by weight of a pharmaceutically acceptablecarrier, all percentages being based on the total weight of thecomposition.

As another aspect of the present invention, a combination of a compoundof the present invention with another anticancer agent is envisaged,especially for use as a medicine, more specifically for use in thetreatment of cancer or related diseases.

For the treatment of the above conditions, the compounds of theinvention may be advantageously employed in combination with one or moreother medicinal agents, more particularly, with other anti-cancer agentsor adjuvants in cancer therapy. Examples of anti-cancer agents oradjuvants (supporting agents in the therapy) include but are not limitedto:

-   -   platinum coordination compounds for example cisplatin optionally        combined with amifostine, carboplatin or oxaliplatin;    -   taxane compounds for example paclitaxel, paclitaxel protein        bound particles (Abraxane™) or docetaxel;    -   topoisomerase I inhibitors such as camptothecin compounds for        example irinotecan, SN-38, topotecan, topotecan hcl;    -   topoisomerase II inhibitors such as anti-tumour        epipodophyllotoxins or podophyllotoxin derivatives for example        etoposide, etoposide phosphate or teniposide;    -   anti-tumour vinca alkaloids for example vinblastine, vincristine        or vinorelbine;    -   anti-tumour nucleoside derivatives for example 5-fluorouracil,        leucovorin, gemcitabine, gemcitabine hcl, capecitabine,        cladribine, fludarabine, nelarabine;    -   alkylating agents such as nitrogen mustard or nitrosourea for        example cyclophosphamide, chlorambucil, carmustine, thiotepa,        mephalan (melphalan), lomustine, altretamine, busulfan,        dacarbazine, estramustine, ifosfamide optionally in combination        with mesna, pipobroman, procarbazine, streptozocin,        telozolomide, uracil;    -   anti-tumour anthracycline derivatives for example daunorubicin,        doxorubicin optionally in combination with dexrazoxane, doxil,        idarubicin, mitoxantrone, epirubicin, epirubicin hcl,        valrubicin;    -   molecules that target the IGF-1 receptor for example        picropodophilin;    -   tetracarcin derivatives for example tetrocarcin A;    -   glucocorticoiden for example prednisone;    -   antibodies for example trastuzumab (HER2 antibody), rituximab        (CD20 antibody), gemtuzumab, gemtuzumab ozogamicin, cetuximab,        pertuzumab, bevacizumab, alemtuzumab, eculizumab, ibritumomab        tiuxetan, nofetumomab, panitumumab, tositumomab, ONTO 328;    -   estrogen receptor antagonists or selective estrogen receptor        modulators or inhibitors of estrogen synthesis for example        tamoxifen, fulvestrant, toremifene, droloxifene, faslodex,        raloxifene or letrozole;    -   aromatase inhibitors such as exemestane, anastrozole, letrazole,        testolactone and vorozole;    -   differentiating agents such as retinoids, vitamin D or retinoic        acid and retinoic acid metabolism blocking agents (RAMBA) for        example accutane;    -   DNA methyl transferase inhibitors for example azacytidine or        decitabine;    -   antifolates for example premetrexed disodium;    -   antibiotics for example antinomycin D, bleomycin, mitomycin C,        dactinomycin, carminomycin, daunomycin, levamisole, plicamycin,        mithramycin;    -   antimetabolites for example clofarabine, aminopterin, cytosine        arabinoside or methotrexate, azacitidine, cytarabine,        floxuridine, pentostatin, thioguanine;    -   apoptosis inducing agents and antiangiogenic agents such as        Bcl-2 inhibitors for example YC 137, BH 312, ABT 737, gossypol,        HA 14-1, TW 37 or decanoic acid;    -   tubuline-binding agents for example combrestatin, colchicines or        nocodazole;    -   kinase inhibitors (e.g. EGFR (epithelial growth factor receptor)        inhibitors, MTKI (multi target kinase inhibitors), mTOR        inhibitors) for example flavoperidol, imatinib mesylate,        erlotinib, gefitinib, dasatinib, lapatinib, lapatinib        ditosylate, sorafenib, sunitinib, sunitinib maleate,        temsirolimus;    -   farnesyltransferase inhibitors for example tipifarnib;    -   histone deacetylase (HDAC) inhibitors for example sodium        butyrate, suberoylanilide hydroxamide acid (SAHA), depsipeptide        (FR 901228), NVP-LAQ824, R306465, JNJ-26481585, trichostatin A,        vorinostat;    -   Inhibitors of the ubiquitin-proteasome pathway for example        PS-341, MLN 0.41 or bortezomib;    -   Yondelis;    -   Telomerase inhibitors for example telomestatin;    -   Matrix metalloproteinase inhibitors for example batimastat,        marimastat, prinostat or metastat.    -   Recombinant interleukins for example aldesleukin, denileukin        diftitox, interferon alfa 2a, interferon alfa 2b, peginterferon        alfa 2b    -   MAPK inhibitors    -   Retinoids for example alitretinoin, bexarotene, tretinoin    -   Arsenic trioxide    -   Asparaginase    -   Steroids for example dromostanolone propionate, megestrol        acetate, nandrolone (decanoate, phenpropionate), dexamethasone    -   Gonadotropin releasing hormone agonists or antagonists for        example abarelix, goserelin acetate, histrelin acetate,        leuprolide acetate    -   Thalidomide, lenalidomide    -   Mercaptopurine, mitotane, pamidronate, pegademase, pegaspargase,        rasburicase    -   BH3 mimetics for example ABT-737    -   MEK inhibitors for example PD98059, AZD6244, CI-1040    -   colony-stimulating factor analogs for example filgrastim,        pegfilgrastim, sargramostim; erythropoietin or analogues thereof        (e.g. darbepoetin alfa); interleukin 11; oprelvekin;        zoledronate, zoledronic acid; fentanyl; bisphosphonate;        palifermin.    -   a steroidal cytochrome P450 17alpha-hydroxylase-17,20-lyase        inhibitor (CYP17), e.g. abiraterone, abiraterone acetate.

The compounds of the present invention also have therapeuticapplications in sensitising tumour cells for radiotherapy andchemotherapy.

Hence the compounds of the present invention can be used as“radiosensitizer” and/or “chemosensitizer” or can be given incombination with another “radiosensitizer” and/or “chemosensitizer”.

The term “radiosensitizer”, as used herein, is defined as a molecule,preferably a low molecular weight molecule, administered to animals intherapeutically effective amounts to increase the sensitivity of thecells to ionizing radiation and/or to promote the treatment of diseaseswhich are treatable with ionizing radiation.

The term “chemosensitizer”, as used herein, is defined as a molecule,preferably a low molecular weight molecule, administered to animals intherapeutically effective amounts to increase the sensitivity of cellsto chemotherapy and/or promote the treatment of diseases which aretreatable with chemotherapeutics.

Several mechanisms for the mode of action of radiosensitizers have beensuggested in the literature including: hypoxic cell radiosensitizers(e.g., 2-nitroimidazole compounds, and benzotriazine dioxide compounds)mimicking oxygen or alternatively behave like bioreductive agents underhypoxia; non-hypoxic cell radiosensitizers (e.g., halogenatedpyrimidines) can be analogoues of DNA bases and preferentiallyincorporate into the DNA of cancer cells and thereby promote theradiation-induced breaking of DNA molecules and/or prevent the normalDNA repair mechanisms; and various other potential mechanisms of actionhave been hypothesized for radiosensitizers in the treatment of disease.

Many cancer treatment protocols currently employ radiosensitizers inconjunction with radiation of x-rays. Examples of x-ray activatedradiosensitizers include, but are not limited to, the following:metronidazole, misonidazole, desmethylmisonidazole, pimonidazole,etanidazole, nimorazole, mitomycin C, RSU 1069, SR 4233, E09, RB 6145,nicotinamide, 5-bromodeoxyuridine (BUdR), 5-iododeoxyuridine (IUdR),bromodeoxycytidine, fluorodeoxyuridine (FudR), hydroxyurea, cisplatin,and therapeutically effective analogs and derivatives of the same.

Photodynamic therapy (PDT) of cancers employs visible light as theradiation activator of the sensitizing agent. Examples of photodynamicradiosensitizers include the following, but are not limited to:hematoporphyrin derivatives, Photofrin, benzoporphyrin derivatives, tinetioporphyrin, pheoborbide-a, bacteriochlorophyll-a, naphthalocyanines,phthalocyanines, zinc phthalocyanine, and therapeutically effectiveanalogs and derivatives of the same.

Radiosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof radiosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour with or withoutadditional radiation; or other therapeutically effective compounds fortreating cancer or other diseases.

Chemosensitizers may be administered in conjunction with atherapeutically effective amount of one or more other compounds,including but not limited to: compounds which promote the incorporationof chemosensitizers to the target cells; compounds which control theflow of therapeutics, nutrients, and/or oxygen to the target cells;chemotherapeutic agents which act on the tumour or other therapeuticallyeffective compounds for treating cancer or other disease. Calciumantagonists, for example verapamil, are found useful in combination withantineoplastic agents to establish chemosensitivity in tumor cellsresistant to accepted chemotherapeutic agents and to potentiate theefficacy of such compounds in drug-sensitive malignancies.

In view of their useful pharmacological properties, the components ofthe combinations according to the invention, i.e. the one or more othermedicinal agent and the compound according to the present invention maybe formulated into various pharmaceutical forms for administrationpurposes. The components may be formulated separately in individualpharmaceutical compositions or in a unitary pharmaceutical compositioncontaining all components.

The present invention therefore also relates to a pharmaceuticalcomposition comprising the one or more other medicinal agent and thecompound according to the present invention together with apharmaceutical carrier.

The present invention further relates to the use of a combinationaccording to the invention in the manufacture of a pharmaceuticalcomposition for inhibiting the growth of tumour cells.

The present invention further relates to a product containing as firstactive ingredient a compound according to the invention and as furtheractive ingredient one or more anticancer agent, as a combinedpreparation for simultaneous, separate or sequential use in thetreatment of patients suffering from cancer.

The one or more other medicinal agents and the compound according to thepresent invention may be administered simultaneously (e.g. in separateor unitary compositions) or sequentially in either order. In the lattercase, the two or more compounds will be administered within a period andin an amount and manner that is sufficient to ensure that anadvantageous or synergistic effect is achieved. It will be appreciatedthat the preferred method and order of administration and the respectivedosage amounts and regimes for each component of the combination willdepend on the particular other medicinal agent and compound of thepresent invention being administered, their route of administration, theparticular tumour being treated and the particular host being treated.The optimum method and order of administration and the dosage amountsand regime can be readily determined by those skilled in the art usingconventional methods and in view of the information set out herein.

The weight ratio of the compound according to the present invention andthe one or more other anticancer agent(s) when given as a combinationmay be determined by the person skilled in the art. Said ratio and theexact dosage and frequency of administration depends on the particularcompound according to the invention and the other anticancer agent(s)used, the particular condition being treated, the severity of thecondition being treated, the age, weight, gender, diet, time ofadministration and general physical condition of the particular patient,the mode of administration as well as other medication the individualmay be taking, as is well known to those skilled in the art.

Furthermore, it is evident that the effective daily amount may belowered or increased depending on the response of the treated subjectand/or depending on the evaluation of the physician prescribing thecompounds of the instant invention. A particular weight ratio for thepresent compound of formula (I) and another anticancer agent may rangefrom 1/10 to 10/1, more in particular from 1/5 to 5/1, even more inparticular from 1/3 to 3/1.

The platinum coordination compound is advantageously administered in adosage of 1 to 500 mg per square meter (mg/m²) of body surface area, forexample 50 to 400 mg/m², particularly for cisplatin in a dosage of about75 mg/m² and for carboplatin in about 300 mg/m² per course of treatment.

The taxane compound is advantageously administered in a dosage of 50 to400 mg per square meter (mg/m²) of body surface area, for example 75 to250 mg/m², particularly for paclitaxel in a dosage of about 175 to 250mg/m² and for docetaxel in about 75 to 150 mg/m² per course oftreatment.

The camptothecin compound is advantageously administered in a dosage of0.1 to 400 mg per square meter (mg/m²) of body surface area, for example1 to 300 mg/m², particularly for irinotecan in a dosage of about 100 to350 mg/m² and for topotecan in about 1 to 2 mg/m² per course oftreatment.

The anti-tumour podophyllotoxin derivative is advantageouslyadministered in a dosage of 30 to 300 mg per square meter (mg/m²) ofbody surface area, for example 50 to 250 mg/m², particularly foretoposide in a dosage of about 35 to 100 mg/m² and for teniposide inabout 50 to 250 mg/m² per course of treatment.

The anti-tumour vinca alkaloid is advantageously administered in adosage of 2 to 30 mg per square meter (mg/m²) of body surface area,particularly for vinblastine in a dosage of about 3 to 12 mg/m², forvincristine in a dosage of about 1 to 2 mg/m², and for vinorelbine indosage of about 10 to 30 mg/m² per course of treatment.

The anti-tumour nucleoside derivative is advantageously administered ina dosage of 200 to 2500 mg per square meter (mg/m²) of body surfacearea, for example 700 to 1500 mg/m², particularly for 5-FU in a dosageof 200 to 500 mg/m², for gemcitabine in a dosage of about 800 to 1200mg/m² and for capecitabine in about 1000 to 2500 mg/m² per course oftreatment.

The alkylating agents such as nitrogen mustard or nitrosourea isadvantageously administered in a dosage of 100 to 500 mg per squaremeter (mg/m²) of body surface area, for example 120 to 200 mg/m²,particularly for cyclophosphamide in a dosage of about 100 to 500 mg/m²,for chlorambucil in a dosage of about 0.1 to 0.2 mg/kg, for carmustinein a dosage of about 150 to 200 mg/m², and for lomustine in a dosage ofabout 100 to 150 mg/m² per course of treatment.

The anti-tumour anthracycline derivative is advantageously administeredin a dosage of 10 to 75 mg per square meter (mg/m²) of body surfacearea, for example 15 to 60 mg/m², particularly for doxorubicin in adosage of about 40 to 75 mg/m², for daunorubicin in a dosage of about 25to 45 mg/m², and for idarubicin in a dosage of about 10 to 15 mg/m² percourse of treatment.

The antiestrogen agent is advantageously administered in a dosage ofabout 1 to 100 mg daily depending on the particular agent and thecondition being treated. Tamoxifen is advantageously administered orallyin a dosage of 5 to 50 mg, preferably 10 to 20 mg twice a day,continuing the therapy for sufficient time to achieve and maintain atherapeutic effect. Toremifene is advantageously administered orally ina dosage of about 60 mg once a day, continuing the therapy forsufficient time to achieve and maintain a therapeutic effect.Anastrozole is advantageously administered orally in a dosage of about 1mg once a day. Droloxifene is advantageously administered orally in adosage of about 20-100 mg once a day. Raloxifene is advantageouslyadministered orally in a dosage of about 60 mg once a day. Exemestane isadvantageously administered orally in a dosage of about 25 mg once aday.

Antibodies are advantageously administered in a dosage of about 1 to 5mg per square meter (mg/m²) of body surface area, or as known in theart, if different. Trastuzumab is advantageously administered in adosage of 1 to 5 mg per square meter (mg/m²) of body surface area,particularly 2 to 4 mg/m² per course of treatment.

These dosages may be administered for example once, twice or more percourse of treatment, which may be repeated for example every 7, 14, 21or 28 days.

The compounds of formula (I), the pharmaceutically acceptable additionsalts, in particular pharmaceutically acceptable acid addition salts,and stereoisomeric forms thereof can have valuable diagnostic propertiesin that they can be used for detecting or identifying the formation of acomplex between a labelled compound and other molecules, peptides,proteins, enzymes or receptors.

The detecting or identifying methods can use compounds that are labelledwith labelling agents such as radioisotopes, enzymes, fluorescentsubstances, luminous substances, etc. Examples of the radioisotopesinclude ¹²⁵I, ¹³¹I, ³H and ¹⁴C. Enzymes are usually made detectable byconjugation of an appropriate substrate which, in turn catalyses adetectable reaction. Examples thereof include, for example,beta-galactosidase, beta-glucosidase, alkaline phosphatase, peroxidaseand malate dehydrogenase, preferably horseradish peroxidase. Theluminous substances include, for example, luminol, luminol derivatives,luciferin, aequorin and luciferase.

Biological samples can be defined as body tissue or body fluids.Examples of body fluids are cerebrospinal fluid, blood, plasma, serum,urine, sputum, saliva and the like.

General Synthetic Routes

The following examples illustrate the present invention but are examplesonly and are not intended to limit the scope of the claims in any way.

Experimental Part

Hereinafter, the term ‘ACN’ means acetonitrile, ‘DCM’ meansdichloromethane, ‘K₂CO₃’ means potassium carbonate, ‘MgSO₄’ meansmagnesium sulphate, ‘MeOH’ means methanol, ‘EtOH’ means ethanol, ‘EtOAc’means ethyl acetate, ‘Et₃N’ means triethylamine, ‘DIPE’ meansdiisopropyl ether, ‘THF’ means tetrahydrofuran, ‘NaH’ means sodiumhydride, ‘NH₄OH’ means ammonium hydroxide, ‘t-BuOH’ means2-methyl-2-propanol, ‘Et₂O’ means diethyl ether, ‘SiOH’ means siliciumhydroxide, monosodium salt, ‘MP’ means melting point. ‘t-BuOMe’ means2-methyl-2-propyloxymethylether, ‘NaHSO₃’ means sodium hydrogenosulfite,DMF means dimethyformamide, XPhos means2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, DME meansdimethyl ether, Pd₂dba₃ means Tris(dibenzylideneacetone)dipalladium(0),Xantphos means 4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene, NaHCO₃means sodium hydrogencarbonate, rt means room temperature, PdCl₂dppfmeans 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride,NaOtBu means sodium tertbutylate, Cs₂CO₃ means cesium carbonate, TBAFmeans tetrabutylammonium fluoride.

Some compounds of the present invention were obtained as salt forms orhydrates or contain some amounts of solvent. Hereinafter, thesecompounds are reported as determined based on elemental analysis.

A. Preparation of the Intermediates Example A1

a) Preparation of intermediates 1 and 2

A solution of 6-nitroquinoline (28.1 g; 161 mmol) and N-bromosuccinimide(28.7 g; 161 mmol) in acetic acid (280 ml) was heated at 50° C. for 17hours. The precipitate solid was filtered and washed with Et₂O, waterand then Et₂O to afford 14.7 g (27%) of intermediate 2 (purity 93%). Theorganic layer was evaporated to dryness and the residue was purified bychromatography over silica gel (mobile phase gradient from 50% petroleumether, 50% DCM to 100% DCM). The pure fractions were collected and thesolvent was evaporated, yielding 2.25 g (4%) of intermediate 2 and 16.6g of a residue that was submitted to a second purification bychromatography over silica gel (mobile phase 50% petroleum 9/1/0.2cyclohexane/diethyl ether/DCM) The pure fractions were collected and thesolvent was evaporated, yielding 14.1 g (28%) of intermediate 1.

b) Preparation of intermediate 3

A solution of intermediate 1 (22 g; 86.5 mmol),1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (20g, 95.5 mmol), an aqueous solution of sodium carbonate 2M (53 ml; 104mmol) in ethylene glycol dimethyl ether (250 ml) were degassed with N₂for 15 min. Tetrakis(triphenylphosphine)palladium0 (4 g; 3.5 mmol) wasadded and the mixture was refluxed for 18 hours. The reaction mixturewas cooled down to room temperature, poured into water. The precipitatewas filtered off and washed with water, with DIPE (twice), thendiethylether and dried to afford 22 g of intermediate 3. Intermediate 3was used without further purification for the next step.

Analogous preparation of intermediate 4

starting from intermediate 1

Analogous preparation of intermediate 33

starting from intermediate 1

c) Preparation of intermediate 5

Intermediate 3 (15 g; 59 mmol) was diluted in MeOH (200 ml) and THF (150mL). Then, Raney Nickel (15 g) was added. The mixture was hydrogenatedunder pressure (3 bars) at room temperature for 1.5 hours. The mixturewas filtered over a pad of Celite®, then washed with DCM and evaporatedto dryness. The reaction was repeated on same amounts and combinedresidues (30 g) were purified by chromatography over silica gel (20-45μm 1000 g, mobile phase gradient from 0.1% NH₄OH, 97% DCM, 3% MeOH to0.1% NH₄OH, 95% DCM, 5% MeOH). The pure fractions were collected and thesolvent was evaporated to afford 17 g (64%) of intermediate 5.

Analogous preparation of intermediate 6

starting from intermediate 4

Analogous preparation of intermediate 47

starting from intermediate 49

d) Preparation of intermediate 7

A solution of intermediate 5 (10.5 g; 46.8 mmol),1-bromo-3,5-dimethoxybenzene (10.1 g; 46.8 mmol), cesium carbonate (45.7g; 140 mmol) and2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl (1.1 g; 2.3mmol) in 2-methyl-2-propanol (280 ml) was degassed under N₂, Thentris(dibenzylideneacetone) dipalladium(0) (2.1 g; 2.3 mmol) was addedand the mixture was stirred at 100° C. for 18 hours. The reactionmixture was diluted with MeOH and filtered over a pad of Celite® andwashed with EtOAc. Water was added to the filtrate and the aqueous layerwas extracted with EtOAc. The organic layer was washed with brine, driedover MgSO₄, filtered and evaporated. The crude product was taken up inEt₂O/CH₃CN, filtered and dried to give 7.9 g (46%) of intermediate 7.

Analogous preparation of intermediate 8

starting from intermediate 6

MS: M⁺(H⁺): 431 (method 1, see analytical part)

Analogous preparation of intermediate 31

starting from intermediate 32

Analogous preparation of intermediate 36

starting from intermediate 37

Analogous preparation of intermediate 39

starting from intermediate 41

Analogous preparation of intermediate 42

starting from intermediate 43

Analogous preparation of intermediate 46

starting from intermediate 47

e) Preparation of intermediate 9 and compound 3

NaH (179 m g; 4.5 mmol, 60% dispersion in mineral oil) was addedportionwise to a solution of intermediate 7 (1 g; 2.8 mmol) inN,N-dimethylformamide (15 ml) at 5° C. under N₂ flow. The reactionmixture was stirred at 5° C. for 1 hour. Then, a solution of(2-bromoethoxy)-tert-butyldimethylsilane (0.77 ml; 3.6 mmol) in DMF (2ml) was added dropwise at 5° C. under N₂ flow. The reaction mixture wasstirred overnight at room temperature. LC/MS showed a conversion of 46%.NaH (125 mg; 3.1 mmol, 60% dispersion in mineral oil) was addedportionwise to the solution and (2-bromoethoxy)-tert-butyldimethylsilane(0.6 ml; 2.8 mmol) was added dropwise and the mixture stirred at roomtemperature for 20 hours. Again NaH (132 mg; 3.3 mmol, 60% dispersion inmineral oil) was added portionwise to the solution and(2-bromoethoxy)-tert-butyldimethylsilane (0.6 ml; 2.8 mmol) was addeddropwise and the mixture stirred at room temperature for 6 hours. Thereaction was poured out onto ice water and EtOAc was added. The organiclayer was separated, washed with K₂CO₃ 10%, brine, dried (MgSO₄),filtered and the solvent was evaporated to dryness. The residue waspurified by chromatography over silica gel (15-40 μm 90 g, mobile phasegradient from 99% DCM, 1% MeOH to 97% DCM, 3% MeOH). to give 0.76 g(53%) of intermediate 9, 0.19 g of fraction 1 and 0.4 g of unreactedintermediate 7.

Fraction 1 was purified by preparative liquid chromatography on(Spherical Silica 5 μm 150×30.0 mm). Mobile phase (Gradient from 100%DCM, 0% MeOH to 93% DCM, 7% MeOH) to afford a residue (95 mg) which wascrystallized from CH₃CN to afford 52 mg (5%) of Compound 3. MP=195-196°C.

g) Preparation of intermediate 11

Methanesulfonyl chloride (0.13 ml; 1.7 mmol) was added dropwise to asuspension of Compound 3 (0.34 g; 0.84 mmol), triethylamine (0.3 ml; 1.9mmol) and 4-dimethylaminopyridine (12 mg; 0.1 mmol) in DCM (7 ml) at 5°C. under N₂. The mixture was stirred at room temperature for 1 hour, andwas then poured out onto ice water and DCM was added. The organic layerwas decanted, dried over MgSO₄, filtered and evaporated to dryness togive 0.58 g of intermediate 11. This compound was used without furtherpurification for the next step.

Example A2

Preparation of intermediate 12

NaH (0.18 g; 4.5 mmol, 60% dispersion in mineral oil) was addedportionwise to a solution of intermediate 7 (1 g; 2.8 mmol) inN,N-dimethylformamide (12 ml) at 5° C. under N₂ flow. The reactionmixture was stirred at 5° C. for 1 hour. Then(3-bromopropoxy)-tert-butyldimethylsilane (0.9 ml; 3.6 mmol) was addeddropwise at 5° C. under N₂ flow. The reaction mixture was stirred 18hours at room temperature. The reaction was poured out onto ice waterand EtOAc was added. The organic layer was separated, washed with K₂CO₃10%, brine, dried (MgSO₄), filtered and the solvent was evaporated todryness to give 1.9 g of intermediate 12. This compound was used withoutfurther purification for the next step.

Analogous preparation of intermediate 30

starting from intermediate 31 and(2-bromoethoxy)tert-butyldimethylsilane

Analogous preparation of intermediate 35

starting from intermediate 36 and(2-bromoethoxy)tert-butyldimethylsilane

Example A2a

Preparation of intermediate 45

and compound 61

NaH 60% in mineral oil (108.16 mg; 2.70 mmol) was added portion wise toa solution of intermediate 46 (486 mg; 1.35 mmol) in DMF (7 mL) at 5° C.under N₂ flow. The reaction mixture was stirred at 5° C. for 30 minutesand then a solution of (2-bromoethoxy)-tert-butyldimethylsilane (435 μL;2.03 mmol) in DMF (3 mL) was added drop wise. The reaction mixture wasallowed to warm to room temperature and stirred overnight. It was thenpoured onto ice water and extracted with EtOAc. The organic layer waswashed with brine, dried over MgSO₄, filtered and the solvent wasevaporated. The crude product was purified by chromatography over silicagel (irregular SiOH, 15-45 μm, 24 g; mobile phase: gradient from 100%DCM, 0% MeOH to 98% DCM, 2% MeOH). The product fractions were collectedand evaporated to dryness yielding 210 mg of intermediate 45 (30%) and174 mg of an impure fraction of compound 61 which was purified bychromatography over silica gel (irregular SiOH, 15-45 μm, 24 g; mobilephase: gradient from 100% DCM, 0% MeOH to 99% DCM, 1% MeOH). The productfractions were collected and evaporated to dryness yielding 113 mg ofthe compound which was crystallized from ACN. The precipitate wasfiltered, washed with ACN, then Et₂O and dried to afford 86 mg ofcompound 61 (16%). MP: 158° C. (DSC).

Example A3

Preparation of intermediate 12

Methanesulfonyl chloride (0.37 ml; 4.8 mmol) was added dropwise to asuspension of compound 4 (1 g; 2.4 mmol), triethylamine (0.8 ml; 5.5mmol) and 4-dimethylaminopyridine (30 mg; 0.2 mmol) in DCM (20 ml) at 5°C. under N₂. The mixture was stirred at room temperature for 1 hour. Thereaction mixture was poured out onto ice water and DCM was added. Theorganic layer was decanted, dried over MgSO₄, filtered and evaporated todryness to give 1.2 g of intermediate 13. This compound was used withoutfurther purification for the next step.

Example A3a

Preparation of intermediate 34

Methanesulfonyl chloride (0.13 mL; 1.69 mmol) was added dropwise to asolution of compound 50 (260 mg; 0.65 mmol) and triethylamine (0.27 mL;1.95 mmol) in DCM (6.63 mL) at 5° C. under N₂. The solution was stirredat room temperature for 15 hours. The solvent was evaporated to give 300mg of intermediate 34 (96%) which was used without any purification inthe next step.

Example A4

Preparation of intermediate 14

NaH (1.3 g; 33.3 mmol, 60% dispersion in mineral oil) was addedportionwise to a solution of intermediate 7 (6 g; 16.6 mmol) inN,N-dimethylformamide (70 ml) at 5° C. under N₂ flow. The reactionmixture was stirred at 5° C. for 30 minutes then3-bromo-1-(trimethylsilyl)-1-propyne (5.2 ml; 33.3 mmol) was addeddropwise at 5° C. under N₂ flow. The reaction mixture was stirred 2hours at room temperature. The reaction mixture was quenched with waterand extracted with EtOAc. The organic layer was decanted, washed withbrine, dried over MgSO₄, filtered and evaporated to dryness to afford8.1 g of intermediate. It was used in the next step without any furtherpurification.

Example A5

Preparation of intermediate 15

A solution of sodium nitrite (0.17 g, 2.45 mmol) in water (1 ml) wasadded dropwise to a solution of3-(1-methyl-1H-pyrazol-4-yl-quinolin-6-yl-amine (0.5 g, 2.2 mmol) in HCl(2.5M in H₂O, 10 ml) at 0° C. The mixture was stirred at 0° C. for 30minutes. Then, a solution of potassium iodide (0.44 g, 2.7 mmol) inwater (1 ml) was added dropwise and the mixture was allowed to rise toroom temperature for 3 hours. The reaction mixture was quenched with asolution of sodium hydroxide (3M, 12 ml) until pH 10, and was extractedwith a mixture of DCM/MeOH 8/2 (3×100 ml). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered and concentratedto dryness. The residue was purified by column chromatography oversilica gel (eluent: dichloromethane/methanol 98/2). The productfractions were collected and the solvent was evaporated, yielding 0.17 g(23%) of intermediate 15.

Alternative preparation of intermediate 15

To a solution of NaI (103.5 g; 691 mmol) in ACN (500 ml) were added asolution of 3-(1-methyl-1H-pyrazol-4-yl)-6-quinolinamine (65 g; 290mmol) in ACN/DMSO (1:1, 220 ml) and 1,1-dimethylethyl ester nitrous acid(44.9 g; 435 mmol). To the above solution was slowly added TFA (2 ml)and heated to 65° C. over 45 minutes and stirred for overnight. Thereaction mixture was concentrated under reduce pressure and washed withsolution of NaHSO₃, water and t-BuOMe, yielding 49.60 g of intermediate15 (51.0%, purity 90%).

Alternative preparation of intermediate 15

To a suspension of 6-bromo-3-(1-methyl-1H-pyrazol-4-yl)-quinoline(intermediate 20) (cas number 1184914-71-3), under argon atmosphere,(0.58 g, 2.0 mmol) in dioxane (10 ml) was added copper iodide (0.038 g,0.2 mmol), N, N-dimethylethylenediamine (0.043 ml, 0.4 mmol) and sodiumiodide (0.603 g, 4 mmol). The reaction mixture was stirred at 120° C.overnight in a sealed tube. The reaction was cooled to room temperature,diluted with EtOAc (15 ml), washed with NH₄OH (33% in H₂O) (10 ml), HCl(aq. 0.1 M) (10 ml) and brine (15 ml). The organic layer was dried(Na₂SO₄) and concentrated to give 0.54 (80%) g of intermediate 15.

Alternative preparation of intermediate 15

A solution of sodium nitrite (7.38 g, 107 mmol) in water (60 ml) wasadded dropwise at 0° C. to a solution of3-(1-methyl-1H-pyrazol-4-yl)quinolin-6-yl-amine (24 g, 107 mmol) inaqueous 3 M HCl (10 ml; 428 mmol). The mixture was stirred at 0° C. for20 minutes and EtOAc (600 mL) was added. Then, a solution of sodiumiodide (16 g, 107 mmol) in water (55 ml) was added drop wise at 0° C.The mixture was stirred at 0° C. for 2 hours, at room temperature for 1hour and then concentrated to dryness. The residue was taken up in amixture of MeOH (500 mL) and DCM (500 mL) and the resulting mixture wassonicated for 15 minutes. The insolubles were filtered through a pad ofCelite® which was rinsed with a mixture of MeOH (300 mL) and DCM (300mL). Silica gel was added to the filtrate and the mixture wasconcentrated.

The residue (red brown solid) was purified by chromatography over silicagel (eluent: gradient from DCM/MeOH: 95/5 to 80/20). The fractionscontaining the product were collected and the solvent was evaporatedgiving 11.6 g of an intermediate fraction which was taken up in a 10%aqueous solution of NaHSO₃ (200 mL). The resulting mixture was extractedwith DCM (3×200 mL). The combined organic layers were dried over Na₂SO₄,filtered and concentrated affording 8.2 g of intermediate 15 (23%).

Preparation of intermediate 20

Under argon atmosphere, sodium nitrite (0.34 g, 4.9 mmol) was addedportionwise to a solution of intermediate 5 (0.85 g, 3.8 mmol) inhydrobromic acid (48% in water, 10 ml) over 5 minutes. The mixture wasthen added to a suspension of copper bromide (0.38 g, 2.7 mmol) in HBr(5 ml) at 65° C. over 5 minutes. The mixture was stirred at 70° C. for 1h, cooled down to room temperature and diluted with water (20 ml). Asolution of sodium hydroxide (3 M, 50 ml) was added until reaching pH=10and the aqueous layer was extracted with a mixture ofdichloromethane/methanol 9/1 (3×250 ml). The organic layers were washedwith brine (300 ml), dried over anhydrous sodium sulfate, filtered andconcentrated to dryness. The residue was purified by columnchromatography over silica gel (mobile phase, 98% DCM, 2% MeOH). Theproduct fractions were collected and the solvent was evaporated toprovide 0.82 g of an off-white solid which was further purified byreverse phase chromatography over silica gel (mobile phase; gradientfrom 60% MeOH, 40% water to 100% MeOH). The product fractions werecollected and the solvent was evaporated to provide 0.505 g (46%) ofintermediate 20.

Example A6

a) Preparation of intermediate 18

A solution of intermediate 15 (5 g; 15 mmol),2-fluoro-3,5-dimethoxybenzenamine (2.8 g; 16.4 mmol), sodiumtert-butoxide (4.3 g; 45 mmol) in dry dioxane (100 ml) was degassedunder N₂, then rac-bis(diphenylphosphino)-1,1′-binaphthyl (465 mg; 0.75mmol) and palladium(II) acetate (47% Pd) (167 mg; 0.75 mmol) were addedand the mixture was heated at 100° C. for 15 hours. The reaction mixturewas cooled down to room temperature and poured out onto ice water andbrine and DCM. The mixture was stirred at room temperature for 30minutes, then filtered through Celite®. The organic layer was washedwith brine then water, was dried over MgSO₄, filtered and evaporated todryness. The crude product was crystallized in DCM, filtered off, theprecipitate was washed with Et₂O and dried under vacuum to give 2.9 g ofintermediate 18 (51%), MP=118° C.

Analogous preparation of intermediate 10

starting from intermediate 15

Example A8

a) Preparation of intermediate 17

A mixture of 2-chloro-4-methoxypyrimidine (2 g; 13.8 mmol),3-hydroxymethylpyrrolidine (1.68 g; 16.6 mmol) and K₂CO₃ (3.8 g; 27.7mmol) in acetonitrile (100 ml) was refluxed for 6 hours. The mixture wascooled down, was poured out onto cooled water and extracted with DCM.The organic layer was dried over MgSO₄, filtered and evaporated todryness. The residue was chromatographed over silica gel (15-40 μm 300g, mobile phase: 0.1% NH₄OH, 97% DCM, 3% MeOH). The product fractionswere collected and the solvent was evaporated to give 1.95 g (67%) ofintermediate 17.

b) Preparation of intermediate 19

Methanesulfonylchloride (3.6 ml; 46.6 mmol) was added dropwise to asuspension of intermediate 17 (1.95 mg; 9.3 mmol) in DCM (15 ml) andtriethylamine (2.4 ml; 16.9 mmol) at 10° C. under N₂. The mixture wasstirred at 10° C. for 1 hour, then iced water was added. The mixture wasextracted with DCM, dried over MgSO₄, filtered and the solvent wasevaporated. The resulting residue (3.8 g) was purified by silica gelchromatography (irregular SiO₂, 15-40 μm; 40 g; eluent: 99% DCM, 1%MeOH). The product fractions were mixed and the solvent was concentratedto afford 2 g (75%) of intermediate 19.

Example A9

Preparation of intermediate 21

A catalytic amount of iodine was added to a suspension of magnesium(0.234 g; 9.63 mmol) in THF (1 mL). The mixture was heated with a hotgun until reflux and allowed to cool to room temperature. 1 ml of asolution of 1-bromo-3,5-dimethoxybenzene (2.09 g; 9.63 mmol) in THF (10mL) was added drop wise and the mixture was heated with a hot gun untilreflux and allowed to cool to room temperature. Then, the solution of1-bromo-3,5-dimethoxybenzene was diluted with THF (5.2 mL) and addeddrop wise over a period of 20 minutes to the reaction mixture which wasrefluxed for 1 hour, allowed to cool to room temperature and directlyengaged in the next step.

Example A10

Preparation of intermediate 22

Pd(Ph₃)₄ (1.04 g; 0.90 mmol) was added to a solution of intermediate 15(3.01 g; 8.98 mmol), N,O-dimethylhydroxylamine hydrochloride (1.93 g;19.8 mmol) and triethylamine (6.51 mL; 46.7 mmol) in toluene (39.3 mL),previously purged with argon. The mixture was then purged with CO andheated at 110° C. for 16 hours under CO atmosphere. The reaction mixturewas diluted with a saturated aqueous solution of K₂CO₃ (250 mL) andextracted with DCM/MeOH (95/5; 3×250 mL). The combined organic layerswere dried over Na₂SO₄, filtered and concentrated under reduce pressure.

The brown residue was combined with another crude prepared from 115 mgof intermediate 15. The resulting residue was purified by chromatographyover silica gel (eluent: DCM/MeOH: 98/2 to 90/10). The product fractionswere collected and the solvent was evaporated to afford 2.38 g ofintermediate 22 (86%).

Example A11

Preparation of intermediate 23

Triethyl phosphonoacetate (1.08 mL; 5.42 mmol) was added drop wise to asuspension of sodium hydride (217 mg; 5.42 mmol) in THF (5 mL) at 0° C.After 1 hour at room temperature, a solution of compound 31 (675 mg;1.81 mmol) in THF (18.3 mL) was added drop wise and the reaction mixturewas heated to reflux for 2 h 30. The reaction mixture was then dilutedwith water (30 mL) and extracted with DCM (3×30 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated underreduce pressure.

The residue (1.38 g; orange oil) was purified by chromatography oversilica gel (eluent: EtOAc/MeOH: 99/1). The pure fractions were mixed andthe solvent was evaporated to afford 720 mg of intermediate 23 (82%; E/Zor Z/E mixture: 65/35). Intermediate 23 was engaged in the next stepwithout any further purification.

Example A12

Preparation of intermediate 24

Methanesulfonyl chloride (0.047 mL; 0.605 mmol) was added dropwise at 0°C. under argon atmosphere to a mixture of compound 34 (0.122 g; 0.302mmol) and Et₃N (0.105 mL; 0.756 mmol) in DCM (5 mL). The reactionmixture was quenched with ice water (5 mL) and extracted with DCM (3×10mL). The organic layer was decanted, dried over Na₂SO₄, filtered andevaporated to dryness to give intermediate 24 which was used as such inthe next step.

Example A13

a) Preparation of intermediate 25

A mixture of 3-bromo-6-nitroquinoline (intermediate 1, CAS: 7101-95-3)(13.8 g; 54.5 mmol),(N-tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-boronic acidpinacol ester (CAS: 286961-14-6) (18.55 g; 59.99 mmol), Pd(Ph₃)₂Cl₂(1.91; 2.73 mmol) and Cs₂CO₃ (35.54 g; 109.07 mmol) was dissolved indioxane (150 mL) and water (60 mL). The mixture was stirred at 80° C.for 2 h, then poured into water. The precipitate was filtered off. Thefiltrate was extracted with DCM and concentrated under vacuum.

The residue was purified by chromatography over silica gel (gradienteluent: Petroleum Ether/EtOAc: 3/1) yielding 7.5 g of intermediate 25(97%).

b) Preparation of intermediate 26

To a solution of intermediate 25 (3 g; 8.44 mmol) in MeOH (250 mL) wasadded Raney Nickel (0.5 g; 8.44 mmol). The mixture was hydrogenatedunder pressure (3 bars) at room temperature overnight. The solution wasfiltered over a pad of Celite® then rinsed with DCM and the solvent wasevaporated to give 2.76 g (100%) of intermediate 26, which was usedwithout further purification in the next step.

c) Preparation of intermediate 27

Under N₂, Pd₂dba₃ (0.632 g; 069 mmol) was added to a previously degassedmixture of intermediate 26 (2.26 g; 6.9 mmol),1-bromo-3,5-dimethoxybenzene (1.5 g; 6.9 mmol), cesium carbonate (6.75g; 20.7 mmol) and XPhos (0.329 g; 0.69 mmol) in 2-methyl-2-propanol(98.4 mL). The mixture was heated at 100° C. for 5 hours. The reactionmixture was poured into water, filtered through a pad of Celite® andwashed with EtOAc. Water was added to the filtrate and the aqueous layerwas extracted with EtOAc. The organic layer was washed with brine, driedover MgSO₄, filtered and the solvent was evaporated. The residue waspurified by chromatography over silica gel (Irregular SiOH, 120 g, 15-40μm: eluent: DCM/MeOH: 100/0 to 97/3). The pure fractions were collectedand the solvent was evaporated to give 2.5 g (78%) of intermediate 27.

Example A14

a) Preparation of intermediate 28

In a round bottom flask, intermediate 25 (1.9 g; 5.35 mmol) and ammoniumchloride (2.86 g; 53.46 mmol) were diluted in THF/MeOH/water (1/1/1)(114 mL). Then, iron (1.49 g; 26.73 mmol) was added and the reactionmixture was refluxed for 4 h. The reaction mixture was filtered over apad of Celite® and rinsed with DCM. The solvent was evaporated. Theaqueous layer was basified with saturated aqueous NaHCO₃, then extractedtwice with DCM. The organic layer were combined, dried over MgSO₄,filtered and concentrated. The residue was purified by chromatographyover silica gel (irregular SiOH, 300 g, 15-40 μm; mobile phase: 99% DCM,1% MeOH). The pure fractions were mixed and the solvent was evaporatedto give 1.1 g of intermediate 28. (63%)

b) Preparation of intermediate 29

A solution of intermediate 28 (1.1 g; 3.38 mmol),1-bromo-3,5-dimethoxybenzene (0.734 g; 3.38 mmol), cesium carbonate (3.3g; 10.14 mmol) and XPhos (161 mg; 0.338 mmol) in 2-methyl-2-propanol (48mL) was degassed under N₂. Pd₂dba₃ (310 mg; 0.338 mmol) was added andthe mixture was stirred at 100° C. for 5 h. The reaction mixture waspoured into water, filtered through a pad of Celite® and washed withEtOAc. Water was added to the filtrate and extracted with AcOEt. Theorganic layer was washed with brine, dried over MgSO₄, filtered and thesolvent was evaporated. The residue was purified by chromatography oversilica gel (irregular SiOH, 120 g, 15-40 μm, eluent: gradient fromDCM/MeOH: 100/0 to 97/3). The pure fractions were mixed and the solventwas evaporated to give 1.37 g of intermediate 29 (87%).

Example A15

Preparation of intermediate 32

A solution of intermediate 33 (1.97 g; 7.87 mmol) and Pd on carbon (10wt %) (0.42 g; 0.393 mmol) in THF (75 ml) and MeOH (75 ml) was stirredunder 1 atm of H₂ at room temperature for 3 hours. The reaction mixturewas filtered though a pad of Celite® and the solvent was concentratedunder vacuum.

The residue was purified by chromatography over silica gel (15-40 μm, 40g, Mobile phase: gradient from 100% DCM to 98% DCM 2% MeOH). The productfractions were collected and evaporated to dryness to give 1.24 g ofintermediate 32 (72%).

Analogous preparation of intermediate 37

starting from intermediate 38

Example A16

Preparation of intermediate 38

This reaction was carried out by 4 pots on 5 g scale each in parallel.

To a solution of 3-bromo-6-nitroquinoline (intermediate 1), CAS:7101-95-3) (5 g; 19.76 mmol) in dioxane (100 mL) was added morpholine(2.06 g; 23.7 mmol), Pd₂dba₃ (904 mg; 0.99 mmol), Xantphos (571 mg; 0.99mmol) and Cs₂CO₃ (12.87 g; 39.5 mmol) under N₂. The mixture was stirredat 110° C. for 25 h under N₂. Then, it was cooled to room temperatureand quenched with water. The aqueous mixture was extracted with DCM(3*300 ml) and the combined organic extracts were washed with brine,dried over Na₂SO₄, filtered and the solvent was concentrated underreduced pressure.

The crude product, coming from the 4 reactions, was purified bychromatography over silica gel (Eluent: gradient DCM/EtOAc from 50/1 to20/1). The desired fractions were collected and evaporated to give 8.25g of intermediate 38 (41%)

Example A17

a) Preparation of intermediate 40

A solution of 3-bromo-6-nitroquinoline (intermediate 1, CAS: 7101-95-3)(3.141 g, 12.41 mmol), pyridine-4-boronic acid pinacol ester (3.055 g,14.89 mmol), Na₂CO₃ (3.95 g, 37.24 mmol) in dioxane (38.6 ml) and water(15.4 ml) was degassed with argon for 15 min prior to the addition ofPdCl₂(dppf) (0.454 g, 0.621 mmol) at room temperature. The suspensionwas stirred under argon at reflux overnight. The reaction mixture wascooled to room temperature. The suspension was filtered through a pad ofCelite®, rinsed with a solution of DCM/methanol (8:2) and the filtratewas concentrated under reduced pressure to afford a dark brown solid(7.15 g).

The crude product was adsorbed on silica gel and purified bychromatography over silica gel (eluent: DCM/acetone: 95:5 to 90:10). Theproduct fractions were collected and the solvent was evaporated toafford 1.54 g of intermediate 40 (49%; brown solid).

Analogous preparation of intermediate 44

Reaction performed in MeOH instead of dioxane

b) Preparation of intermediate 41

A suspension of intermediate 40 (1.542 g, 6.137 mmol) in THF (15.7 ml)and MeOH (5.7 ml) was purged with argon prior to the addition of asuspension of raney Nickel, 50% slurry in water (0.396 g, 6.751 mmol) inMeOH (10 ml) at room temperature. The brown suspension was purged withargon, purged with hydrogen and stirred under hydrogen (1 atm.) at roomtemperature overnight. The suspension was filtered through a pad ofCelite®, washed with a solution of DCM/methanol (1:1) and the filtratewas concentrated under reduced pressure to afford a brown orange solid(1.25 g).

The crude product was adsorbed on silica gel and purified chromatographyover silica gel (eluent: DCM/methanol 100:0 to 95:5). The productfractions were collected and the solvent was evaporated to afford 400 mgof intermediate 41 (29%; green yellow solid).

Analogous preparation of intermediate 43

starting from intermediate 44

Example A18

a) Preparation of intermediate 48

A mixture of 3-bromo-6-nitroquinoline (intermediate 1, CAS: 7101-95-3)(7.23 g, 28.62 mmol); 1-(triisopropylsilyl)-1H-pyrrol-3-ylboronic acidpinacol ester (CAS: 365564-11-0) (10 g; 28.62 mmol), Pd(Ph₃)₂Cl₂ (0.603g; 0.86 mmol) and potassium acetate (5.6 g; 57.24 mmol) in DME (100 mL)and water (20 mL) was stirred at 80° C. overnight. The reaction mixturewas filtered and concentrated. DCM was added to induce crystalization.The residue was filtered affording 4.5 g of intermediate 48.

b) Preparation of intermediate 49

Sodium hydride, 60% in mineral oil (2.2 g; 55 mmol) was added drop wiseat 0° C. to a solution of intermediate 48 (4.5 g; 18.81 mmol) in DMF(100 mL). Methyl iodide (8.016 g; 56.47 mmol) was added. The mixture wasstirred at room temperature for 2 h. Water was added to inducecrystalization. The residue was filtered and washed with cooled wateraffording 4.82 g intermediate 49.

B. Preparation of the Compounds Example B1

Preparation of compound 1

KOH (932 mg; 14.1 mmol) was dissolved in THF (7 ml) and H₂O (distilled,0.17 ml). Intermediate 7 (341 mg; 0.95 mmol), then tetrabutylammoniumbromide (76.5 mg, 0.24 mmol) were added to the mixture and stirred atroom temperature for 5 minutes. The reaction mixture was heated at 50°C. for 1 hour. Then N-(2-chloroethyl)-2-propanamine, hydrochloride (225mg, 1.4 mmol) was added and the reaction mixture was stirred at 50° C.for 18 hours. N-(2-chloroethyl)-2-propanamine, hydrochloride (76 mg,0.48 mmol) was added and the reaction mixture was stirred at 50° C. for5 hours. Water was added and the reaction mixture was extracted withEtOAc. The organic layer was washed with brine, dried over MgSO₄,filtered and evaporated to dryness. The crude product was purified bychromatography over silica gel (5 μm, mobile phase: Gradient from 0.2%NH₄OH, 98% DCM, 2% MeOH to 0.8% NH₄OH, 92% DCM, 8% MeOH). The desiredproduct fraction was collected and the solvent was evaporated. Theresidue was dissolved in MeOH, 2 drops of HCl (37%) were added and thereaction mixture was stirred at room temperature for 2 minutes. Themixture was evaporated, taken up with CH₃CN and crystallized from CH₃CNto afford 41 mg of compound 1 (9%) as a chlorohydrate.

Analogous preparation of compound 2

starting from intermediate 18

Alternative Preparation of Compound 1

A mixture of intermediate 11 (0.58 g; 1.2 mmol) in isopropylamine (9 ml;117 mmol) was heated at 90° C. for 4 hours in sealed tube. The reactionmixture was cooled to room temperature and the mixture was evaporateduntil dryness. The crude product was purified by chromatography oversilica gel (5 μm; mobile phase: gradient from 100% DCM to 0.5% NH₄OH,95% DCM, 5% MeOH). The pure fractions were collected and the solvent wasevaporated to afford 0.17 g (31%). The residue was taken up withCH₃CN/EtOH, 3 drops of HCl 37% were added and the product wascrystallized from CH₃CN/EtOH to afford 0.16 g (25%) of compound 1 as achlorohydrate.

Analogous preparation of compound 51

1.88 HClstarting from intermediate 34

Example B1a

Preparation of compound 42

Intermediate 10 (500 mg; 1.26 mmol) then tetrabutylammonium bromide(203.3 mg; 0.63 mmol) were added to a solution of KOH (1.25 g; 18.9mmol) in 2-methyltetrahydrofuran (15 mL) and water (1 mL) at rt. Thereaction mixture was heated at 50° C. for 1 h, then2-isopropylaminoethylchloride hydrochloride (CAS 6306-61-2) (279 mg;1.77 mmol) was added. The reaction mixture was heated at 50° C. for 20hours. The reaction mixture was cooled to rt, then poured into water andbrine. EtOAc was added and the organic layer was washed with brine,dried over MgSO₄, filtered and evaporated to dryness. The residue (0.7g) was purified by chromatography over silica gel (irregular SiOH, 15-40μm 30 g; mobile phase: 0.4% NH₄OH, 98% DCM, 2% MeOH). The pure fractionswere collected and evaporated to dryness to give 130 mg which wascrystallized from Et₂O to give 88 mg (14%) of compound 42. M.P.: 75° C.(gum, Kofler).

Example B1b

Preparation of compound 43

as a HCl Salt

Intermediate 10 (0.6 g; 1.51 mmol), then tetrabutylammonium bromide (244mg; 0.76 mmol) were added to a solution of KOH (1.5 g; 22.7 mmol) in2-methyltetrahydrofuran (30 mL) and water (1.2 mL) at rt. The reactionmixture was heated at 50° C. for 1 h, then (2-chloroethyl)methylamine(212.4 mg; 2.3 mmol) was added. The reaction mixture was heated at 50°C. for 15 hours. The reaction mixture was cooled to rt, then poured intowater and brine. EtOAc was added and the organic layer was washed withbrine, dried over MgSO₄, filtered and evaporated to dryness. The residue(0.8 g) was purified by chromatography over silica gel (Sperical Silica,5 μm 150×30.0 mm; mobile phase: gradient from 0.2% NH₄OH, 98% DCM, 2%MeOH to 1.2% NH₄OH, 88% DCM, 12% MeOH). The pure fractions werecollected and evaporated to dryness to give 82 mg an intermediatefraction (82 mg) which was solubilized in Et₂O. HCl (3 eq.) was addedand the precipitate was filtered off, washed with Et₂O and dried undervacuum to give 71 mg (8%) of compound 43. M.P.: 180° C. (gum, Kofler).

Example B2

Preparation of compound 3

A 1M solution of tetrabutylammonium fluoride in THF (4.8 ml; 4.8 mmol)was added dropwise to a solution of intermediate 9 (2 g; 4 mmol) in THF(40 ml) at room temperature. The reaction mixture was stirred at roomtemperature for 18 hours. The mixture was poured out onto ice water andEtOAc was added. The mixture was basified with K₂CO₃ 10% and the organiclayer was separated, washed with brine, dried (MgSO₄), filtered and thesolvent was evaporated. The residue was triturated from diethyl ether,filtered and dried under vacuum, yielding 0.34 g (21%) of compound 3.

Example B3

Preparation of compound 4

A 1M solution of tetrabutylammonium fluoride in THF (3.33 ml; 3.33 mmol)was added dropwise to a solution of intermediate 12 (1.48 g, 2.8 mmol)in THF (50 ml) at room temperature. The reaction mixture was stirred atroom temperature for 1 h 30. The mixture was poured out onto ice waterand EtOAc was added and the mixture was basified with K₂CO₃ 10%. Thereaction mixture was extracted, the organic layer was washed with brine,dried over MgSO₄, filtered and concentrated under reduced pressure. Theresidue (1.9 g) was purified by chromatography over silica gel (40 g,15-40 μm, mobile phase 97/3/0.1 DCM/MeOH/NH₄OH) to afford 1.08 g ofcompound 4.

Example B3a

Preparation of compound 50

Tetrabutylammonium fluoride (1M in THF) (1.17 mL; 1.17 mmol) was addeddropwise to a solution of intermediate 30 (600 mg; 1.17 mmol) in THF (25ml) at 10° C. Then, the reaction mixture was stirred at room temperaturefor 15 hours and the mixture was poured onto ice water. EtOAc was addedand the mixture was basified with 10% aqueous K₂CO₃. The organic layerwas separated, washed with brine, dried over MgSO₄, filtered and thesolvent was evaporated to dryness. The residue (550 mg) was purified waspurified by chromatography over silica gel (irregular SiOH, 15-40 μm 30g; mobile phase: 0.1% NH₄OH, 97% DCM, 3% MeOH, flow rate 20 ml/min). Thefractions containing the product were combined and the solvent wasevaporated. 2 fractions with different purity of compound 50 wereobtained: 200 mg of a fraction A (43%) and 190 mg of a fraction B (41%).The fraction B was partitioned between EtOAc and brine. The organiclayer was washed twice with brine, dried over MgSO₄, filtered and thesolvent was evaporated to dryness to give an intermediate fraction whichwas taken up with Et₂O. The precipitate was filtered and dried undervacuum to give 56 mg of compound 50 (12%). MP: 111° C. (DSC)

Analogous preparation of compound 54

starting from intermediate 35

Example B3b

Preparation of compound 61

TBAF (1M in THF) (4.06 mL; 4.06 mmol) was added drop wise to a solutionof intermediate 45 (210 mg; 0.41 mmol) in THF (3.5 mL) at 5° C. under N₂flow. The reaction mixture was stirred at room temperature for 6 hours,then poured onto 10% aqueous K₂CO₃ and extracted with EtOAc. The organiclayer was washed with brine, dried over MgSO₄, filtered and the solventwas evaporated. The crude product was purified by chromatography oversilica gel (irregular SiOH, 15-45 μm 24 g; mobile phase: gradient from100% DCM, 0% MeOH to 99% DCM, 1% MeOH). The product fractions werecollected and evaporated to dryness to give 113 mg of a compound whichwas crystallized from ACN. The precipitate was filtered, washed withACN, then Et₂O and dried yielding 93 mg of compound 61 (57%). MP: 158°C. (DSC).

Example B4

Preparation of compound 5

(1.78 HCl 0.88 H₂O 0.17 C₆H₁₄O 0.1 C₂H₆O)

A mixture of intermediate 13 (1.4 g; 2.8 mmol) in2,2,2-trifluoroethylamine (10 ml) was heated at 90° C. for 4 hours insealed tube. The reaction mixture was cooled to room temperature and themixture was evaporated until dryness. The crude product was purified bychromatography over silica gel (Spherical silica, 5 μm, 300 g; mobilephase 0.1% NH₄OH, 98% DCM, 2% MeOH). The product fractions werecollected and the solvent was evaporated. The residue (0.6 g) waspurified by achiral SFC on (AMINO 6 μm 150×21.2 mm, mobile phase (0.3%isopropylamine, 75% CO₂, 25% MeOH)). The product fractions werecollected and the solvent was evaporated. The residue (0.4 g) wasdissolved in MeOH then 3 drops of HCl were added. The mixture wasevaporated and crystallized from ACN and washed with DIPE to afford 0.34g of compound 5 (20%)

Analogous preparation of compound 19

Example B5

Preparation of compound 6

A mixture of intermediate 14 (8.1 g; 17.2 mmol) and K₂CO₃ (4.6 g; 34.4mmol) in MeOH (150 ml) was stirred at room temperature for 2 hours. Thereaction mixture was washed with water and extracted with CH₂Cl₂. Thenthe organic layer was dried (MgSO₄), filtered and the solvent wasevaporated. The crude product was purified by chromatography over silicagel (40 g, mobile phase 98/2 CH₂Cl₂/MeOH). The pure fractions werecollected and the solvent was evaporated to afford 5.5 g (80%) ofcompound 6.

Example B6

Preparation of compound 7

Under N₂, NaH (64 mg; 1.6 mmol, 60% dispersion in mineral oil) was addedportionwise to a solution of intermediate 7 (0.3 g; 0.84 mmol) in DMF(30 ml) at 5° C. The solution was stirred 30 minutes at 10° C. Asolution of intermediate 19 (0.35 g; 1.22 mmol) in DMF (10 ml) was addeddropwise. The mixture was heated at 60° C. overnight. The solution waspoured out into cooled water, the product was extracted with EtOAc, theorganic layer was dried over MgSO₄, filtered and evaporated to dryness.The residue was purified by chromatography over silica gel (5 μm, mobilephase g Gradient from 70% Heptane, 2% MeOH, 28% EtOAc to 20% MeOH, 80%EtOAc). The desired fractions were collected and the product wascrystallized from Et₂O, yielding 100 mg (22%) of compound 7 (MP: 132° C.(DSC)).

Example B7

Preparation of compound 8

Under N₂ flow, NaH (0.05 g; 1.25 mmol, 60% dispersion in mineral oil)was added to a solution of intermediate 7 (0.3 g; 0.8 mmol) inN,N-dimethylformamide (12 ml) at 0° C. The suspension was stirred 1 hourat 0° C. and 2-(chloromethyl)pyrimidine (0.14 g, 1.0 mmol) was added.The reaction was stirred for 24 hours at room temperature. The mixturewas poured into ice-water and EtOAc was added. The organic layer wasseparated, dried over MgSO₄, filtered and the filtrate was evaporateduntil dryness. The residue (0.84 g) was purified by chromatography oversilica gel (5 μm; mobile phase gradient from 70% Heptane, 2% MeOH, 28%EtOAc to 20% MeOH, 80% EtOAc). The pure fractions were collected and thesolvent was evaporated. The residue (0.12 g) was crystallized from Et₂O.The precipitate was filtered off and dried to afford 0.087 g (23%) ofcompound 8. (MP: 151° C. (DSC))

Analogous preparation of compound 9

using 2-(chloromethyl)-N,N-dimethyl-1H-Imidazole-1-sulfonamide

Analogous preparation of compound 49

starting from intermediate 27 using2-(chloromethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

Analogous preparation of compound 45

starting from intermediate 29 using2-(chloromethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

Analogous preparation of compound 53

starting from intermediate 31 using2-(chloromethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

Analogous preparation of compound 56

starting from intermediate 36 using2-(chloromethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

Analogous preparation of compound 58

starting from intermediate 39 and2-(chloromethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

Analogous preparation of compound 60

starting from intermediate 42 and2-(chloromethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

Analogous preparation of compound 63

starting from intermediate 46 and2-(chloromethyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide

Example B8

Preparation of compound 10

(2.17 HCl 1.09 H₂O)

NaH (0.3 g; 7.2 mmol, 60% dispersion in mineral oil) was addedportionwise to a solution of 2-pyrrolidinone (0.56 ml; 7.2 mmol) inN,N-dimethylformamide (25 ml) at 5° C. under N₂ flow. The reactionmixture was stirred at 5° C. for 1 hour. Then a solution of intermediate13 (1.2 g, 2.4 mmol) in N,N-dimethylformamide (15 ml) was added dropwiseat 5° C. The reaction mixture was stirred overnight at room temperature.The reaction mixture was poured out onto ice water and EtOAc was added.The organic layer was separated, washed with brine, dried (MgSO₄),filtered and the solvent was evaporated. The residue (1.1 g) waspurified by chromatography over silica gel (15-40 μm 300 g; mobile phase40% Heptane, 10% MeOH, 50% EtOAc). The pure fractions were collected andthe solvent was evaporated. The residue (0.35 g) was dissolved in MeOHand 3 eq. of HCl 5N were added. The precipitate was filtered and driedto afford 0.35 g (28%) of compound 10 (MP: 142° C. (Kofler)).

Analogous preparation of compound 47 starting from intermediate 13 and1,1-trifluoro-N-[(2S)-2-pyrrolidinyl-methyl]methanesulfonamide

Example B9

Preparation of compound 11

Intermediate 7 (0.22 g; 0.61 mmol) was added to a solution of potassiumhydroxide (0.6 g; 9.2 mmol), tetrabutylammonium bromide (0.078 g; 0.25mmol) in dry THF (3 ml) and water (0.05 ml). The reaction mixture wasstirred at 50° C. for 30 minutes then 3-bromopropylamine hydrochloride(0.34 g; 1.6 mmol) was added portionwise and stirred at 50° C. for 48hours. The reaction mixture was cooled to room temperature. The reactionwas poured out onto ice water and EtOAc was added. The organic layer wasseparated, washed with brine, dried (MgSO₄), filtered and the solventwas evaporated. The residue (0.22 g) was purified by chromatography oversilica gel (5 μm; mobile phase gradient from 0.2% NH₄OH, 98% DCM, 2%MeOH to 1.3% NH₄OH, 87% DCM, 13% MeOH). The pure fractions werecollected and concentrated to give 0.068 g (27%) of compound 11.

Example B10

Preparation of compound 12

The reaction was performed in anhydrous conditions under argonatmosphere. Chloro(1-methylethyl)-magnesium (2M in THF, 0.18 ml, 0.36mmol) was added to a solution of intermediate 15 (0.1 g, 0.3 mmol) inTHF (1 ml) at 0° C. The reaction mixture was stirred at 0° C. for 1hour. Then, a solution of 3,5-dimethoxybenzaldehyde (0.06 g, 0.36 mmol)in THF (0.50 ml) was added dropwise at 0° C. The reaction mixture wasstirred at 0° C. for 1 hour. The reaction mixture was quenched with asaturated solution of ammonium chloride (3 ml) and was extracted withdichloromethane (3×5 ml). The organic layers were dried over anhydroussodium sulphate, filtered and concentrated to dryness. The residue waspurified by column chromatography over silica gel (mobile phase: 98%DCM, 2% MeOH) The product fractions were collected and the solvent wasevaporated, yielding 0.053 g (47%) of compound 12 (MP: 184-193° C.).

Preparation of compound 12

Preparation of compound 38

Preparation of compound 37

Compound 12 was also prepared as follows:

Under N₂ at 10° C., sodium borohydride (60.8 mg; 1.61 mmol) was added toa solution of compound 31 (300 mg; 0.8 mmol) in MeOH (15 mL). Thesolution was stirred at 10° C. for 45 minutes then, poured onto cooledwater. The product was extracted with DCM (twice). A saturated aqueoussolution of NaCl was added to the aqueous layer which was then extractedwith DCM (twice). The organic layers were combined, dried over MgSO₄,filtered and evaporated to dryness.

The residue (300 mg) was purified by chromatography over silica gel(Irregular SiOH, 20-45 μm, 24 g; Mobile phase: 0.1% NH₄OH, 97% DCM, 3%MeOH, flow rate: 25 ml/min). The fractions containing product were mixedand the solvent was evaporated to dryness affording 204 mg of anintermediate fraction which was taken up with Et₂O. The precipitate wasfiltered and washed with Et₂O to give 126 mg of compound 12 (41%). MP:240° C. (Mettler-Toledo).

106 mg of compound 12 were purified by chiral SFC (stationary phase:CHIRALCEL OJ-H 5 μm 250×20 mm; mobile phase: 60% CO₂, 40% MeOH). Theproduct fractions were collected and evaporated to dryness yielding 44mg of compound 37 (16%), 174° C. (Kofler) and 45 mg of compound 38(16%), 174° C. (Kofler).

Example B11

Preparation of compound 15

NaH (79 mg; 2.0 mmol, 60% dispersion in mineral oil) was addedportionwise to a solution of intermediate 18 (500 mg; 1.3 mmol) in N,N-dimethylformamide (10 ml) at 5° C. under N₂ flow. The reaction mixturewas stirred at 5° C. for 30 minutes then3-bromo-1-(trimethylsilyl)-1-propyne (0.31 ml; 2.0 mmol) was added at 5°C. under N₂ flow. The reaction mixture was stirred for 15 hours at roomtemperature. The reaction mixture was quenched with water and EtOAc wasadded. The organic layer was decanted, washed with brine, dried overMgSO₄, filtered and evaporated to dryness. The crude product wascrystallized from Et₂O, yielding 320 mg of compound 15 (58%, MP: 120°C.).

Analogous preparation of compound 20

starting from intermediate 10

Example B12

Preparation of compound 22

The reaction was performed in anhydrous conditions under argonatmosphere. A solution of intermediate 8 (2.6 g, 6.1 mmol) in DMF (21ml) was stirred at 0° C. for 15 minutes. Then NaH (1.46 g, 36.6 mmol,60% dispersion in mineral oil) was added and the reaction mixture wasstirred at 0° C. for 15 minutes. Then, 2-propanamine,N-(2-chloroethyl)-, hydrochloride (5.3 g, 33.6 mmol) was addedportionwise at 0° C. The brown suspension was stirred at roomtemperature overnight. The reaction mixture was cooled to 0° C. Asaturated solution of ammonium chloride (30 ml) was added and theaqueous layer was extracted with ethyl acetate (2×30 ml). The organiclayer was washed with brine (3×40 ml), dried over MgSO₄, filtered andconcentrated under reduced pressure. The crude product was purified bychromatography over silica gel (mobile phase; phase gradient from 90%DCM, 10% acetone to 90% DCM, 10% acetone followed by another gradientfrom 95% DCM, 5% MeOH to 90% DCM, 10% MeOH). The products fractions werecollected and the solvents were evaporated, yielding 2.955 g of compound22 (94%).

Example B13

Preparation of

NaH (240 mg, 6.1 mmol) was added portionwise to a solution ofintermediate 7 (1.1 g, 3.05 mmol) in DMF (12 ml) at 5° C. under N₂ flow.The reaction mixture was stirred at 5° C. for 1 hour then1,2-epoxy-3,3,3-trifluoropropane (0.32 ml, 3.6 mmol) was added dropwiseat 5° C. under N₂ flow. The reaction mixture was stirred for 1 hour at5° C. then allowed to reach room temperature. The reaction was stirredat room temperature for 1 hour. The reaction was poured out onto icewater and EtOAc was added. The organic layer was separated, washed withbrine, dried (MgSO₄), filtered and the solvent was evaporated. Theresidue (1.7 g) was purified by chromatography over silica gel (15-40 μm300 g, mobile phase 0.1% NH₄OH, 98% DCM, 2% MeOH). The pure fractionswere collected and the solvent was evaporated to afford 450 mg ofcompound 23. The enantiomers were separated by chiral SFC on). (mobilephase; gradient from 65% CO₂, 35% EtOH to 50% CO₂, 50% EtOH). The purefractions were collected and the solvent was evaporated, yielding 185 mgof fraction 1 and 170 mg of fraction 2. Fraction 1 was crystallized fromDIPE, the precipitate was filtered off and dried to give 126 mg (9%, MP:116° C. (Kofler); [α]_(D)=+120.3° (c=0.39, DMF, 20° C.) of compound 24

Fraction 2 was crystallized from DIPE, the precipitate was filtered offand dried to give 120 mg (8%, MP: 118° C. (Kofler), [α]_(D)=−122.6°(c=0.34, DMF, 20° C.) of compound 25

Example B14

Preparation of compound 31

Intermediate 21 (16.2 mL; 9.64 mmol, 0.59 M in THF) (CAS: 322640-05-1)was added drop wise to a solution of intermediate 22 (2.38 g; 8.03 mmol)in THF (40 mL) at 0° C. The mixture was heated at 50° C. for 3 days,then, poured onto a saturated aqueous NH₄Cl solution (50 mL) andextracted with EtOAc (3×50 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduce pressure. Theresulting residue was purified by chromatography over silica gel(eluent: DCM/MeOH: 98/2 to 90/10). The product fractions were mixed andthe solvent was evaporated yielding 2.01 g of an intermediate fraction(pale orange solid) which was again purified by chromatography oversilica gel (eluent: gradient from DCM/MeOH: 95/5 to 90/10). Thefractions were collected and the solvent evaporated affording 2fractions:

-   -   Fraction A: 987 mg of compound 31    -   Fraction B 880 mg of compound 31

Fraction B was purified by reverse phase chromatography (eluent: DCM).The fraction containing the product were mixed and the solventevaporated giving additional 570 mg of compound 31.

In total, 1.56 g (52%) of compound 31 were obtained. MP: 190° C.(Kofler)

Example B15

Preparation of a Mixture of Compound 32 and

Compound 33

Magnesium (433 mg; 17.8 mmol) was added portion wise to a solution ofintermediate 23 (660 mg; 1.62 mmol) in a mixture of MeOH (15 mL) and THF(2 mL) at room temperature and the reaction mixture was stirred for 2hours at this temperature. Additional magnesium (433 mg; 17.8 mmol) wasadded and the reaction mixture was stirred for another 3 hours. Thereaction mixture was quenched with an aqueous saturated solution NH₄Cl(100 mL). Water (50 mL) was added and the mixture was extracted with DCM(3×50 mL). The organic layers were combined, dried over Na₂SO₄, filteredand concentrated to dryness.

The residue (713 mg; orange gum) was purified by chromatography oversilica gel (eluent: DCM/EtOAc: 3/7). The pure fractions were mixed andthe solvent was evaporated to afford 385 mg of a mixture of compound 32and 33, which were engaged in the next step without any furtherpurification.

Example B16

Preparation of compound 41

1.41 HCl

A mixture of intermediate 24 (0.145 g; 0.302 mmol) and isopropylamine (3mL; 35.2 mmol) in 1,4-dioxane (2 mL) was stirred at 90° C. for 16 hoursin a sealed tube under argon atmosphere. The reaction mixture wasevaporated to dryness. The residue (293 mg) was purified bychromatography over silica gel (irregular SiOH, 15-40 μm; mobile phase:0.5% NH₄OH, 5% MeOH, 95% DCM). The product fractions were collected andevaporated to dryness. The free base (0.108 g; 80%) was dissolved inMeOH and a solution of HCl 1.25M in iPrOH (1 mL) followed by Et₂O (10mL) were added. The reaction mixture was evaporated to dryness and driedunder vacuum to give 0.084 g (56%) of compound 41 as a hydrochloride.M.P.: >300° C. (DSC)

Example B17

Preparation of compound 44

Under N₂, NaH (55.5 mg; 1.39 mmol) was added to a solution ofintermediate 7 (250 mg; 0.69 mmol) in DMF (10 mL) at 0° C. Then, thesuspension was stirred for 1 h at 0° C. and(S)-(+)-5-(Hydroxymethyl)-2-pyrrolidinone p-toluenesulfonate (CAS51693-17-5) (187 mg; 0.69 mmol) was added. The reaction mixture wasstirred overnight at rt. Additional(S)-(+)-5-(Hydroxymethyl)-2-pyrrolidinone p-toluenesulfonate (CAS51693-17-5) (94 mg; 0.35 mmol) was added. The reaction mixture wasstirred at it 2 days. The solution was poured into cooled water and theproduct was extracted with EtOAc. The organic layer was dried overMgSO₄, filtered and evaporated to dryness. The residue was purified bycolumn chromatography over silica gel (Irregular SiOH, 20-45 μm, 30 g;mobile phase: 0.1% NH₄OH, 97% DCM, 3% MeOH). The fractions containingthe product were collected and the solvent was evaporated to dryness.The residue (130 mg) was taken up with Et₂O. The precipitate wasfiltered and dried under vacuum. The resulting solid (35 mg) waspurified by chromatography over silica gel (5 μm, 150×30.0 mm; mobilephase: gradient from 50% Heptane, 3% MeOH, 27% EtOAc to 0% Heptane, 25%MeOH, 75% EtOAc). The pure fractions were collected and evaporated togive 24 mg (8%) of compound 44. MP: gum at 102° C. (Kofler).

C. Conversions of the Compounds

Conversion C1

Preparation of compound 16

A suspension of compound 6 (0.85 g; 2.2 mmol),2-chloro-4-methoxypyrimidine (0.22 g; 1.5 mmol) and Et₃N (2.5 mL; 18.3mmol) in DMSO (18 ml) was degassed under N₂ flow.Dichlorobis(triphenylphosphine)-palladium (0.2 g; 0.3 mmol) andcopper(I) iodide (29 mg; 0.15 mmol) were added and the reaction mixturewas stirred at 60° C. for 40 minutes. The reaction mixture was cooleddown to room temperature, poured out onto water and EtOAc was added. Themixture was filtered off on a pad of Celite®. The organic layer wasseparated, washed with brine, dried (MgSO₄), filtered and evaporated todryness. The residue (1.4 g) was purified by chromatography over silicagel (20-40 μm, 300 g; mobile phase, 98% DCM, 2% MeOH). The purefractions were collected and evaporated to dryness. The residue (0.4 g)was crystallized from CH₃CN/MeOH/Et₂O, the precipitate was filtered anddried to give 0.24 g (31%) of compound 16 (MP: 203° C. (DSC)).

Analogous preparation of compound 17

starting from compound 6 using 2-bromo-3-methoxypyridine

Analogous preparation of compound 26

starting from compound 15 using 2-bromo-3-methoxypyridine

Analogous preparation of compound 27

starting from compound 20 using 2-bromo-3-methoxypyridine

Analogous preparation of compound 48

starting from compound 6 using 2-iodo-1-methyl-1H-imidazoleConversion C2

Preparation of compound 18

HCl (4M in dioxane; 2.2 ml; 8.7 mmol) was added to a solution ofcompound 9 (480 mg; 0.87 mmol) in ACN (20 ml) and the reaction mixturewas heated at 50° C. for 15 hours. The mixture was poured out onto ice,basified with K₂CO₃ and extracted with DCM. The organic layer was driedover MgSO₄, filtered and evaporated till dryness. The obtained residuewas purified by chromatography over silica gel (5 μm; mobile phase,gradient from 0.2% NH₄OH, 98% DCM, 2% MeOH to 1% NH₄OH, 89% DCM, 10%MeOH). The pure fractions were collected and the solvent was evaporated.The residue (160 mg) was taken up in Et₂O, filtered and dried, yielding103 mg of compound 18 (27%; MP: 196° C.).

Analogous preparation of compound 55

1.86 HClstarting from compound 56

Analogous preparation of compound 57

starting from compound 58

Analogous preparation of compound 59

starting from compound 60

Analogous preparation of compound 62

starting from compound 63Conversion C3

Preparation of compound 13

2HCl

A solution of compound 21 (0.46 g; 1.07 mmol) ethylene carbonate (104mg; 0.18 mmol) and sodium hydroxide (4 mg; 0.107 mmol) in DMF (8.3 mL)was purged with argon and stirred at reflux for 2 hours. LC/MS showed afull conversion. The reaction mixture was cooled down to roomtemperature. A saturated solution of ammonium chloride was added and themixture was stirred at room temperature for 20 min. The organic layerwas decanted and successively washed with a saturated solution of sodiumbicarbonate (20 mL), brine (50 mL), dried over MgSO₄, filtered andevaporated to afford a brown yellow solid. The residue was purified bychromatography over silica gel (mobile phase; phase gradient from 95%DCM, 5% MeOH to 90% DCM, 10% MeOH). The product fractions were collectedand the solvent was evaporated to provide a yellow foam (370 mg, 73%).The product was triturated in acetonitrile and the suspension wasfiltered off to provide 62 mg (12%) of compound 13. The filtrate wasconcentrated under reduced pressure to afford 308 mg of a yellow foam.(0.308 g, 0.648 mmol) was dissolved in DCM (3 ml) and HCl (2.2 ml,2M/Et₂O, 6.476 mmol) was added dropwise at room temperature. The orangesuspension was stirred at room temperature for 1 hour. The reactionmixture was concentrated under reduced pressure. The resulting solid wastriturated with Et₂O and filtered off on glass-frit, yielding 250 mg ofcompound 13 (75%) as a chlorohydrate (MP: 86-115° C.).

Conversion C4

Preparation of compound 14

The reaction was performed in anhydrous conditions under argon.

To a solution of compound 21 (0.618 g, 1.4 mmol) and K₂CO₃ (0.396 g, 2.9mmol) in DMF (6.4 ml) was added dropwise methylsulfonylethene (0.14 ml,1.6 mmol) at room temperature. The yellow solution was stirred at 70° C.for 1 hour. A saturated solution of ammonium chloride (10 ml) was addedand the aqueous layer was extracted with EtOAc (20 ml). The organiclayer was washed with brine (50 ml), dried over Na₂SO₄, filtered andconcentrated. The crude product was purified by chromatography oversilica gel (mobile phase; phase gradient from 95% DCM, 5% MeOH to 90%DCM, 10% MeOH). The product fractions were collected and the solventswere evaporated. The residue was triturated with diethylether and thesuspension was filtered off, yielding 616 mg of compound 14 (80%) (MP:129° C. (DSC)).

Conversion C5

Preparation of compound 21

To a solution of compound 22 (1.56 g, 3.0 mmol) in MeOH (282 ml) wasadded dropwise HCl (37%; 9.3 ml) at room temperature. The orangesolution was stirred at room temperature for 1 hour. The TLC showed afull conversion into the desired compound. The reaction mixture wascooled to 0° C. Then, a saturated solution of sodium carbonate was addeduntil a pH=12 and the mixture was stirred at room temperature for 1hour. The aqueous layer was extracted twice with EtOAc. The organiclayer was washed with brine, dried over Na₂SO₄, filtered andconcentrated under reduced pressure to afford a yellow gum (1.7 g). Thecrude product was purified by chromatography over silica gel (mobilephase, gradient from 95% DCM, 5% MeOH to 85% DCM, 15% MeOH). The productfractions were collected and the solvent was evaporated, yielding 1.068g of compound 21 (82%).

Conversion C6

Preparation of compound 28,

compound 29 and

compound 30

Diethyl cyanomethylphosphonate (0.249 mL; 1.53 mmol) was added inanhydrous conditions under Ar atmosphere to a suspension of sodiumhydride (61.4 mg; 1.53 mmol; 60% in oil) in THF (1.5 mL) at 0° C. After1 hour at room temperature, a solution of compound 31 (191 mg; 0.51mmol) in THF (5.1 mL) was added drop wise and the reaction mixture washeated to reflux for 2 h 30. It was then diluted with water (10 mL) andextracted with DCM (3×10 mL). The combined organic layers were driedover Na₂SO₄, filtered and concentrated under reduced pressure.

The residue (368 mg; red oil) was purified by chromatography over silicagel (SiOH, 15-40 μm, eluent: EtOAc/MeOH: 99/1). After evaporation of thesolvent, 3 different fractions were obtained:

-   -   Fraction A: 187 mg of compound 28 (colorless oil; mixture of        compound 29 and compound 30: 6/4)    -   Fraction B: 9 mg of compound 29 (colorless oil)    -   Fraction C: 8 mg of compound 30 (colorless oil)

Fraction A was purified by achiral SFC (stationary phase:DIETHYLAMINOPROPYL 5 μm 150×21.2 mm; mobile phase: 90% CO₂, 10% MeOH).The product fractions were collected and evaporated to dryness yieldingadditional 53 mg of compound 29, M.P.: 86° C. (gum, Kofler), andadditional 31 mg of compound 30. MP: 166° C. (Kofler). Based on fractionA, B and C, the overall yield is 73%

Conversion C7

Preparation of compound 34,

compound 35 and

compound 36

Lithium aluminium hydride (67.7 mg; 1.78 mmol) was added portion wise toa solution of mixture of compound 32 and compound 33 (385 mg; 0.892mmol) in THF (10 mL) at 0° C. and the reaction mixture was stirred for 1hour 20 minutes at this temperature. EtOAc (20 mL) was added slowlyfollowed by water (30 mL) and the mixture was extracted by DCM (2×80mL). The organic layers were combined, dried over Na₂SO₄, filtered andconcentrated.

The residue (385 mg; pale yellow gum) was purified by chromatographyover silica gel (15-40 μm, eluent: DCM/MeOH: 98/2). The productfractions were mixed and the solvent was evaporated to give 247 mg of apale yellow gum which was sonicated in ACN (5 mL). The resulting solidwas filtered off on a glass frit, rinsed with ACN (2×5 mL) and driedunder vacuum (80° C., 16 h) to afford 117 mg (32%) of compound 34 as awhite solid. MP=131° C. (DSC).

80 mg of this fraction were purified by chiral SFC (stationary phase:CHIRALCEL OJ-H 5 μm 250×20 mm; mobile phase: 65% CO₂, 35% iPrOH). Theproduct fractions were collected and evaporated to dryness yielding 37mg of compound 35, M.P.: gum 56° C. (Kofler) and 38 mg of compound 36.M.P.: gum at 56° C. (Kofler).

Conversion C8

Preparation of compound 39 and

compound 40

Sodium borohydride (0.064 g; 1.69 mmol) was added at room temperatureunder argon atmosphere to a solution of compound 28 (0.096 g; 0.242mmol) in pyridine (1.5 mL) and MeOH (0.5 mL). The reaction mixture wasrefluxed for 18 hours and cooled to room temperature. Additional sodiumborohydride (0.018 g; 0.484 mmol) was added and the reaction mixture wasrefluxed for 5 hours more, quenched with ice water (15 mL) and extractedwith EtOAc (3×10 mL). The combined organic layers were dried overNa₂SO₄, filtered and evaporated to dryness. The residue (100 mg) waspurified by chromatography over silica gel (irregular SiOH, 15-40 μm;mobile phase: gradient from 2% MeOH, 98% DCM to 10% MeOH, 90% DCM). Theproduct fractions were collected and evaporated to dryness to give 2fractions:

-   -   Fraction A: 0.045 g which were triturated in Et₂O to give 0.032        g (33%) of compound 39. M.P.: 172° C. (DSC)    -   Fraction B: 0.011 g (11%) of compound 40.        Conversion C9

Preparation of compound 46

A mixture of compound 45 (0.25 g; 0.385 mmol) and 6N HCl (5.14 mL) indioxane (5.14 mL) was heated at 100° C. overnight. The mixture wasbasified by solid K₂CO₃ and evaporated till dryness. The residue wastaken up by DCM/MeOH/NH4OH (90/10/1) and filtered. The filtrate wasevaporated. The residue was purified by chromatography over silica gel(irregular SiOH, 24 g; 15-40 μm, mobile phase (90% DCM, 10% MeOH, 1%NH₄OH). The pure fractions were mixed and the solvent was evaporated.The residue was taken up by Et₂O, filtered and dried to give 36 mg (21%)of compound 46. MP: gum at 110° C. (Kofler)

Analogous preparation of compound 48a

starting from compound 49Conversion C9a

Preparation of compound 52

To a solution of compound 53 (490 mg; 0.77 mmol) in ACN (29.5 mL) wasadded drop wise at 5° C., HCl 4M in dioxane (1.92 ml; 7.66 mmol). Thereaction mixture was then heated at 50° C. for 18 h and thenconcentrated under reduced pressure. The reaction mixture was taken upwith DCM and washed with 10% aqueous K₂CO₃ and brine, dried over MgSO₄,filtered and concentrated under reduced pressure. The residue (360 mg)was purified by chromatography over silica gel (irregular SiOH, 15-40 μm30 g, Mobile phase: 0.1% NH₄OH, 97% DCM, 3% MeOH, flow rate 20 ml/min).The pure fraction were mixed and concentrated under reduced pressure toafford 90 mg of an intermediate compound which was taken up in Et₂O. Theprecipitate was filtered to afford 59 mg of compound 52 (18%). MP: 133°C. (DSC)

The following compounds were prepared according to reaction protocols ofone of the above Examples using alternative starting materials asappropriate.

In the table =CX (or =BX) indicates that the preparation of thiscompound is described in Conversion X (or Method BX).

In the table ˜CX (or ˜BX) indicates that this compound is preparedaccording to Conversion X (or Method BX).

As understood by a person skilled in the art, compounds synthesisedusing the protocols as indicated may exist as a solvate e.g. hydrate,and/or contain residual solvent or minor impurities. Compounds isolatedas a salt form, may be integer stoichiometric i.e. mono- or di-salts, orof intermediate stoichiometry.

TABLE A1 physico-chemical data If physio-chemical data were generatedmultiple times for a compound then all data is listed Melting (KoflerHPLC MS LC/GC/ Co. Point (K) or Rt M + MS No. Compound structure Method(° C.) DSC) (min) (H⁺) method  3

=B2 195 K 2.46 405 1  4

=B3 184 (gum) K 2.52 419 1  1

=B1 227 K 2.31 446 1 as a HCl salt  5

=B4 186 (gum) K 3.05 500 1 as a HCl salt  6

=B5 142 K 2.86 399 1 16

=Cl 203 DSC 2.9 507 1 17

~Cl 155 DSC 2.81 506 1  8

=B7 151 DSC 2.63 453 1  9

~B7 110 (gum) 2.83 548 1 18

=C2 198 DSC 2.35 441 1 10

=B8 142 K 2.59 486 1 as a HCl salt 11

=B9 2.13 4.18 1 27

~Cl 184 DSC 2.72 548 1 24

=B13 R or S 116 K 2.88 473 1 25

=B13 S or R 119 K 2.88 473 1 19

~B4 103 DSC 2.82 474 1 22

=B12 10.11 516 3  7

=B6 132 DSC 3.19 552 1  2

~B1  70 (gum) 2.28 464 1 12

=B10 183-192 12.31 336 2 13

=C3 86-115° C. Buchi M-560 9.16 476 3 as a HCl salt 14

=C4 129 DSC 11.58 538 2 15

=B11 120 K 26

~Cl 142 K 2.74 524 1 23

=B13 20

~B11 21

=C5 11.49 432 1 47

~B8 115 DSC 2.66 633 1 42

=B1a 75 K 2.29 482 1 48

~Cl 160 K 2.63 479 1 43

=B1b 180 (gum) K 2.11 454 1 as a HCl salt 44

B17 108 (gum) K 2.39 458 1   48a

~C9 Gum at  84 K 1.97 444 1 46

=C9 Gum at 110 K 1.98 442 1 50

=B3a 111 DSC 3.03 401 1 51

B1 180° C. (gum) K 2.87 442 1 as a HCl salt 52

B9a 133 DSC 2.82 437 1 54

~B3a 118 DSC 2.48 410 1 55

220 K 2.35 446 1 as a HCl salt 57

113-126 Buchi M-560 8.79 438 3 58

161 DSC 10.51 545 3 59

110-123 Buchi M-560 8.7 438 3 60

82-86 Buchi M-560 10.64 545 3 61

158 DSC 2.75 404 1 62

197 DSC 2.60 440 1 38

174 K 2.32 376 1 37

174 K 2.32 376 1 31

190 K 2.76 374 1 29

Gum at  86 K 2.78 397 1 30

166 K 2.73 397 1 34

131 DSC 9.81 404 3 35

Gum at  56 K 2.34 404 1 36

Gum at  56 K 2.34 404 1 41

>300   DSC 9.26 445 3 as a HCl salt 39

172 DSC 10.53 399 3 40

— — 9.35 417 3Analytical PartLC/GC/NMR

The LC/GC data reported in Table A1 were determined as follows.

General Procedure A

The LC measurement was performed using a UPLC (Ultra Performance LiquidChromatography) Acquity (Waters) system comprising a binary pump withdegasser, an autosampler, a diode-array detector (DAD) and a column asspecified in the respective methods below, the column is hold at atemperature of 40° C. Flow from the column was brought to a MS detector.The MS detector was configured with an electrospray ionization source.The capillary needle voltage was 3 kV and the source temperature wasmaintained at 130° C. on the Quattro (triple quadrupole massspectrometer from Waters). Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Waters-Micromass MassLynx-Openlynx datasystem.

Method 1

In addition to the general procedure A: Reversed phase UPLC was carriedout on a Waters Acquity BEH (bridged ethylsiloxane/silica hybrid) C18column (1.7 μm, 2.1×100 mm) with a flow rate of 0.343 ml/min. Two mobilephases (mobile phase A: 95% 7 mM ammonium acetate/5% acetonitrile;mobile phase B: 100% acetonitrile) were employed to run a gradientcondition from 84.2% A and 15.8% B (hold for 0.49 minutes) to 10.5% Aand 89.5% B in 2.18 minutes, hold for 1.94 min and back to the initialconditions in 0.73 min, hold for 0.73 minutes. An injection volume of 2μl was used. Cone voltage was 20V for positive and negative ionizationmode. Mass spectra were acquired by scanning from 100 to 1000 in 0.2seconds using an interscan delay of 0.1 seconds.

General Procedure B

The HPLC measurement was performed using an HPLC 1100/1200 (Agilent)system comprising a quaternary pump with degasser, an autosampler, adiode-array detector (DAD) and a column as specified in the respectivemethods below, the column is held at a room temperature. The MS detector(MS-Agilent simple quadripole) was configured with an electrospray-APCIionization source. Nitrogen was used as the nebulizer gas. Dataacquisition was performed with a Chemstation data system.

Method 2

In addition to the general procedure B: Reversed phase HPLC was carriedout on a Nucleosil C18 column (3 μm, 3×150 mm) with a flow rate of 0.42ml/min. Two mobile phases (mobile phase A: Water TFA 0.1%; mobile phaseB: 100% acetonitrile) were employed to run a gradient condition from 98%A for 3 minutes, to 100% B in 12 minutes, 100% B for 5 minutes, thenback to 98% A in 2 minutes, and reequilibrated with 98% A for 6 minutes.An injection volume of 2 μl was used. The capillary voltage was 2 kV,the corona discharge was held at 1 ρA and the source temperature wasmaintained at 250° C. A variable voltage was used for the fragmentor.Mass spectra were acquired in electrospray ionization and APCI inpositive mode, by scanning from 100 to 1100 amu.

Method 3

In addition to the general procedure B: Reversed phase HPLC was carriedout on a Agilent Eclipse C18 column (5 μm, 4.6×150 mm) with a flow rateof 1 ml/min. Two mobile phases (mobile phase A: Water TFA 0.1%; mobilephase B: 100% acetonitrile) were employed to run a gradient conditionfrom 98% A for 3 minutes, to 100% B in 12 minutes, 100% B for 5 minutes,then back to 98% A in 2 minutes, and reequilibrated with 98% A for 6minutes. An injection volume of 2 μl was used. The capillary voltage was2 kV, the corona discharge was held at 1 μA and the source temperaturewas maintained at 250° C. A variable voltage was used for thefragmentor. Mass spectra were acquired in electrospray ionization andAPCI in positive mode, by scanning from 80 to 1000 amu.

DSC:

Melting point (M.P.) were taken with a Kofler hot bar or a Büchi MeltingPoint M-560 but also for a number of compounds, melting points (m.p.)were determined with a DSC1 Star^(e) System (Mettler-Toledo). Meltingpoints were measured with a temperature gradient of 10° C./minute.Maximum temperature was 350° C. Values are peak values.”

OR:

Optical Rotation is measured with a polarimeter 341 Perkin Elmer.

The polarized light is passed through a sample with a path length of 1decimeter and a sample concentration of 0.250 to 0.500 gram per 100milliliters.

[α]_(d) ^(T): (red rotation×100)/(1.000 dm×concentration).

^(d) is sodium D line (589 nanometer).

T is the temperature (° C.).

Oreg.:

Compound 47: [α]_(d): −28.16° (589 nm, c 0.245 w/v %, DMF, 20° C.)

The below NMR experiments were carried out using a Bruker Avance 500 anda Bruker Avance DRX 400 spectrometers at ambient temperature, usinginternal deuterium lock and equipped with reverse triple-resonance (¹H,¹³C, ¹⁵N TXI) probe head for the 500 MHz and with reversedouble-resonance (¹H, ¹³C, SEI) probe head for the 400 MHz.

Chemical shifts (δ) are reported in parts per million (ppm).

Compound 1:

¹H NMR (500 MHz, DMSO-d6) δ 9.16 (s, 1H), 9.05 (s, 2H), 8.71 (br.s, 1H),8.42 (s, 1H), 8.11 (s, 1H), 8.02 (d, J=9.3 Hz, 1H), 7.60 (d, J=9.3 Hz,1H), 7.50 (d, J=2.7 Hz, 1H), 6.42-6.58 (m, 3H), 4.17 (t, J=7.6 Hz, 2H),3.92 (s, 3H), 3.75 (s, 6H), 3.34 (spt, J=6.4 Hz, 1H), 3.15 (m, 2H), 1.25(d, J=6.4 Hz, 6H).

Compound 16:

NMR (500 MHz, DMSO-d6) δ 9.00 (d, J=2.1 Hz, 1H), 8.43 (d, J=5.9 Hz, 1H),8.38 (s, 1H), 8.35 (d, J=2.1 Hz, 1H), 8.08 (s, 1H), 7.87 (d, J=9.1 Hz,1H), 7.46 (d, J=2.6 Hz, 1H), 7.40 (dd, J=9.1, 2.6 Hz, 1H), 6.91 (d,J=5.9 Hz, 1H), 6.40 (d, J=2.1 Hz, 2H), 6.33 (t, J=2.1 Hz, 1H), 4.93 (s,2H), 3.90 (s, 3H), 3.86 (s, 3H), 3.72 (s, 6H).

Compound 17:

¹H NMR (500 MHz, DMSO-d6) δ 9.00 (d, J=2.2 Hz, 1H), 8.37 (s, 1H), 8.33(d, J=2.2 Hz, 1H), 8.08 (s, 1H), 8.06 (d, J=4.4 Hz, 1H), 7.86 (d, J=9.1Hz, 1H), 7.48-7.43 (m, 2H), 7.41 (dd, J=9.1, 2.6 Hz, 1H), 7.33 (dd,J=8.5, 4.4 Hz, 1H), 6.42 (d, J=2.2 Hz, 2H), 6.32 (t, J=2.2 Hz, 1H), 4.89(s, 2H), 3.90 (s, 3H), 3.76 (s, 3H), 3.72 (s, 6H).

Compound 42:

¹H NMR (400 MHz, DMSO-d₆) δ 8.88 (d, J=2.02 Hz, 1H), 8.32 (s, 1H), 8.22(d, J=2.02 Hz, 1H), 8.03 (s, 1H), 7.78 (d, J=9.09 Hz, 1H), 7.07 (dt,J=2.78, 9.09 Hz, 2H), 6.96 (d, J=2.78 Hz, 1H), 3.92 (s, 6H), 3.90 (s,3H), 3.76 (t, J=7.07 Hz, 2H), 2.78 (t, J=7.07 Hz, 2H), 2.63-2.72 (m,1H), 1.57 (br. s., 1H), 0.94 (d, J=6.06 Hz, 6H)

Compound 43:

¹H NMR (500 MHz, DMSO-d₆) δ 9.23 (s, 1H), 9.19 (br. s., 2H), 8.83 (br.s., 1H), 8.44 (s, 1H), 8.07-8.15 (m, 2H), 7.54 (d, J=8.20 Hz, 1H), 7.42(br. s., 1H), 7.17 (t, J=8.20 Hz, 1H), 4.07-4.14 (m, 2H), 3.89-3.98 (m,9H), 3.17 (br. s., 2H), 2.62 (t, J=5.20 Hz, 3H)

Compound 44:

¹H NMR (500 MHz, DMSO-d₆) δ 8.94 (d, J=2.21 Hz, 1H), 8.35 (s, 1H), 8.24(d, J=2.21 Hz, 1H), 8.05 (s, 1H), 7.85 (s, 1H), 7.80 (d, J=8.83 Hz, 1H),7.33 (dd, J=2.52, 8.83 Hz, 1H), 7.29 (d, J=2.52 Hz, 1H), 6.35 (d, J=2.21Hz, 2H), 6.28 (t, J=2.21 Hz, 1H), 3.90 (s, 3H), 3.79-3.86 (m, 3H), 3.70(s, 6H), 2.20-2.31 (m, 1H), 2.03-2.15 (m, 2H), 1.63-1.73 (m, 1H)

Compound 2:

¹H NMR (DMSO-d₆, 500 MHz): δ (ppm) 8.86 (d, J=2.2 Hz, 1H), 8.33 (s, 1H),8.21 (d, J=2.2 Hz, 1H), 8.04 (s, 1H), 7.75 (d, J=9.1 Hz, 1H), 7.11 (dd,J=9.1, 2.7 Hz, 1H), 6.96 (d, J=2.7 Hz, 1H), 6.70 (dd, J=6.5, 3.0 Hz,1H), 6.61 (dd, J=5.5, 3.0 Hz, 1H), 3.89 (s, 3H), 3.86 (s, 3H), 3.81 (t,J=6.9 Hz, 2H), 3.76 (s, 3H), 2.78 (t, J=6.9 Hz, 2H), 2.69 (spt, J=6.1Hz, 1H), 1.74 (br. s., 1H), 0.94 (d, J=6.1 Hz, 6H)

Compound 46:

¹H NMR (DMSO-d₆, 500 MHz): δ (ppm) 11.91 (br. s., 1H), 8.87 (d, J=2.2Hz, 1H), 8.01 (d, J=2.2 Hz, 1H), 7.80 (d, J=9.1 Hz, 1H), 7.54 (d, J=2.5Hz, 1H), 7.45 (dd, J=9.1, 2.5 Hz, 1H), 7.00 (s, 1H), 6.83 (s, 1H), 6.50(br. s., 1H), 6.39 (d, J=2.2 Hz, 2H), 6.21 (t, J=2.2 Hz, 1H), 4.99 (s,2H), 3.68 (s, 6H), 3.40-3.47 (m, 2H), 2.96 (t, J=5.7 Hz, 2H), 2.72 (br.s., 1H), 2.44 (s, 2H)

Compound 29:

¹H NMR (400 MHz, CDCl₃): δ 9.14 (1H, d, J=2.4 Hz), 8.24 (1H, d, J=2.4Hz), 8.14 (1H, d, J=8.4 Hz), 8.04 (1H, d, J=2.0 Hz), 7.94 (1H, s), 7.83(1H, s), 7.59 (1H, dd, J=8.4 Hz, J=2.0 Hz), 6.56 (1H, t, J=2.4 Hz), 6.44(2H, d, J=2.4 Hz), 5.86 (1H, s), 4.02 (3H, s), 3.76 (6H, s).

Compound 30:

¹H NMR (400 MHz, CDCl₃): δ 9.10 (1H, d, J=2.0 Hz), 8.14 (1H, d, J=2.0Hz), 8.08 (1H, d, J=8.8 Hz), 7.91 (1H, s), 7.80 (1H, s), 7.73 (1H, d,J=2.0 Hz), 7.64 (1H, dd, J=8.8 Hz, J=2.0 Hz), 6.60 (3H, s), 5.89 (1H,s), 4.01 (3H, s), 3.81 (6H, s).

Pharmacological Part

Biological Assays A

FGFR1 (Enzymatic Assay)

In a final reaction volume of 30 μL, FGFR1 (h) (25 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 5 μM ATP in the presence of compound(1% DMSO final). After incubation for 60 minutes at room temperature thereaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in RFU (Relative FluorescenceUnits). In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value.

FGFR2 (Enzymatic Assay)

In a final reaction volume of 30 μL, FGFR2 (h) (150 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 0.4 μM ATP in the presence of compound(1% DMSO final). After incubation for 60 minutes at room temperature thereaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in (Relative Fluorescence Units).In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value.

FGFR3 (Enzymatic Assay)

In a final reaction volume of 30 μL, FGFR3 (h) (40 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 25 μM ATP in the presence of compound(1% DMSO final). After incubation for 60 minutes at room temperature thereaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in RFU (Relative FluorescenceUnits). In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value.

FGFR4 (Enzymatic Assay)

In a final reaction volume of 30 μL, FGFR4 (h) (60 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 5 μM ATP in the presence of compound(1% DMSO final). After incubation for 60 minutes at room temperature thereaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in RFU (Relative FluorescenceUnits). In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value.

KDR (VEGFR2) (Enzymatic Assay)

In a final reaction volume of 30 μL, KDR (h) (150 ng/ml) was incubatedwith 50 mM HEPES pH 7.5, 6 mM MnCl₂, 1 mM DTT, 0.1 mM Na₃VO₄, 0.01%Triton-X-100, 500 nM Btn-Flt3 and 3 μM ATP in the presence of compound(1% DMSO final). After incubation for 120 minutes at room temperaturethe reaction was stopped with 2.27 nM EU-anti P-Tyr, 7 mM EDTA, 31.25 nMSA-XL-665 and 0.02% BSA which was present for 60 minutes at roomtemperature. Time-Resolved Fluorescence Resonance Energy Transfer(TR-FRET) signal (ex340 nm. Em 620 nm, em 655 nm) was measuredafterwards and results are expressed in RFU (Relative FluorescenceUnits). In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value.

Ba/F3-FGFR1 (Minus IL3 or Plus IL3) (Cellular Proliferation Assay)

In a 384 well plate, 100 nl of compound dilution in DMSO was sprayedbefore adding 50 μl cell culture medium (phenol red free RPMI-1640, 10%FBS, 2 mM L-Glutamine and 50 μg/ml Gentamycin) containing 20000 cellsper well of Ba/F3-FGFR1-transfected cells. Cells were put in anincubator at 37° C. and 5% CO₂. After 24 hours, 10 μl of Alamar Bluesolution (0.5 mM K₃Fe(CN)₆, 0.5 mM K₄Fe(CN)₆, 0.15 mM Resazurin and 100mM Phosphate Buffer) was added to the wells, incubated for 4 hours at37° C. and 5% CO₂ before RFU's (Relative Fluorescence Units) (ex. 540nm., em. 590 nm.) were measured in a fluorescence plate reader.

In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value. As a counterscreenthe same experiment was performed in the presence of 10 ng/ml murineIL3.

Ba/F3-FGFR3 (Minus IL3 or Plus IL3) (Cellular Proliferation Assay)

In a 384 well plate, 100 nl of compound dilution in DMSO was sprayedbefore adding 50 μl cell culture medium (phenol red free RPMI-1640, 10%FBS, 2 mM L-Glutamine and 50 μg/ml Gentamycin) containing 20000 cellsper well of Ba/F3-FGFR3-transfected cells. Cells were put in anincubator at 37° C. and 5% CO₂. After 24 hours, 10 μl of Alamar Bluesolution (0.5 mM K₃Fe(CN)₆, 0.5 mM K₄Fe(CN)₆, 0.15 mM Resazurin and 100mM Phosphate Buffer) was added to the wells, incubated for 4 hours at37° C. and 5% CO₂ before RFU's (Relative Fluorescence Units) (ex. 540nm., em. 590 nm.) were measured in a fluorescence plate reader.

In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value. As a counterscreenthe same experiment was performed in the presence of 10 ng/ml murineIL3.

Ba/F3-KDR (Minus IL3 or Plus IL3) (Cellular Proliferation Assay)

In a 384 well plate, 100 nl of compound dilution in DMSO was sprayedbefore adding 50 μl cell culture medium (phenol red free RPMI-1640, 10%FBS, 2 mM L-Glutamine and 50 μg/ml Gentamycin) containing 20000 cellsper well of Ba/F3-KDR-transfected cells. Cells were put in an incubatorat 37° C. and 5% CO₂. After 24 hours, 10 μl of Alamar Blue solution (0.5mM K₃Fe(CN)₆, 0.5 mM K₄Fe(CN)₆, 0.15 mM Resazurin and 100 mM PhosphateBuffer) was added to the wells, incubated for 4 hours at 37° C. and 5%CO₂ before RFU's (Relative Fluorescence Units) (ex. 540 nm., em. 590nm.) were measured in a fluorescence plate reader.

In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value. As a counterscreenthe same experiment was performed in the presence of 10 ng/ml murineIL3.

Ba/F3-Flt3 (Minus IL3 or Plus IL3) (Cellular Proliferation Assay)

In a 384 well plate, 100 nl of compound dilution in DMSO was sprayedbefore adding 50 μl cell culture medium (phenol red free RPMI-1640, 10%FBS, 2 mM L-Glutamine and 50 μg/ml Gentamycin) containing 20000 cellsper well of Ba/F3-Flt3-transfected cells. Cells were put in an incubatorat 37° C. and 5% CO₂. After 24 hours, 10 μl of Alamar Blue solution (0.5mM K₃Fe(CN)₆, 0.5 mM K₄Fe(CN)₆, 0.15 mM Resazurin and 100 mM PhosphateBuffer) was added to the wells, incubated for 4 hours at 37° C. and 5%CO₂ before RFU's (Relative Fluorescence Units) (ex. 540 nm., em. 590nm.) were measured in a fluorescence plate reader.

In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value. As a counterscreenthe same experiment was performed in the presence of 10 ng/ml murineIL3.

Ba/F3-FGFR4 (Cellular Proliferation Assay)

In a 384 well plate, 100 nl of compound dilution in DMSO was sprayedbefore adding 50 μl cell culture medium (phenol red free RPMI-1640, 10%FBS, 2 mM L-Glutamine and 50 μg/ml Gentamycin) containing 20000 cellsper well of Ba/F3-FGFR4-transfected cells. Cells were put in anincubator at 37° C. and 5% CO2. After 24 hours, 10 μl of Alamar Bluesolution (0.5 mM K₃Fe(CN)₆, 0.5 mM K₄Fe(CN)₆, 0.15 mM Resazurin and 100mM Phosphate Buffer) was added to the wells, incubated for 4 hours at37° C. and 5% CO₂ before RFU's (Relative Fluorescence Units) (ex. 540nm., em. 590 nm.) were measured in a fluorescence plate reader.

In this assay, the inhibitory effect of different compoundconcentrations (range 10 μM to 0.1 nM) was determined and used tocalculate an IC₅₀ (M) and pIC₅₀ (−log IC₅₀) value.

Data for the compounds of the invention in the above assays are providedin Table A2. (If data were generated multiple times for a compound ordifferent batches were tested, average values are reported)

BAF3- BAF3- BAF3- BAF3- BAF3- BAF3- FGFR3 FGFR3 KDR KDR FLT3 FLT3 BAF3-BAF3- (MIN (PLUS (MIN (PLUS (MIN (PLUS FGFR1 FGFR1 IL3 IL3 IL3 IL3 IL3IL3 BAF3- FGFR FGFR hFGFR FGFR VEGFR (MIN (PLUS Alamar Alamar AlamarAlamar Alamar Alamar FGFR Comp. 1 2 3 4 KDR IL3 IL3 Blue- Blue Blue BlueBlue Blue 4 No. pIC50 pIC50 pIC50 pIC50 pIC50 pIC50) pIC50) pIC50)pIC50) pIC50) pIC50) pIC50) pIC50) (pIC50) 1 8.455 8.305 8.1 7.86 7.137.4 <5 7.555 <5 5.635 <5 ~5 <5 7.19 3 7.86 7.83 8.38 7.42 7.04 6.31 5.36.33 <5 5.65 <5 5.52 <5 6.11 4 7.72 7.87 8.23 7.51 6.86 6.26 5.15 6.17<5 5.45 <5 5.35 <5 5.87 5 7.59 7.5 7.64 7.04 6.61 5.79 ~5.04 5.67 <55.18 <5 5.06 <5 5.5 6 7.82 7.52 7.87 6.82 6.37 5.7 5.13 5.79 <5 5.07 <55.2 <5 5.4 16 8.03 7.81 7.87 7.43 6.05 >8 5.45 >8 <5 <5 <5 5.19 5.048.21 17 7.08 6.92 7.23 6.56 <6 7.35 5.09 7.63 <5 <5 <5 <5 <5 6.98 7 6.08<6 6.04 <6 <6 <5 <5 <5 <5 <5 <5 <5 <5 <5 12 6.53 6.38 6.63 <6.03 <6<5.03 <5 ~5.075 <5 <5 <5 <5.47 <5.47 <5 8 8.11 7.7 7.49 6.93 6.09 6.27<5 6.14 <5 <5 <5 <5.47 <5.47 5.64 9 8.25 8.11 7.96 6.84 6.78 6.14 <56.17 <5 <5 <5 <5 <5 5.18 10 7.46 7.89 7.81 7.08 7.09 6.03 <5 6.2 <5 5.11<5 <5 <5 5.63 11 8.44 8.64 8.47 7.7 7.35 6.67 <5 6.97 <5 5.42 <5 <5 <56.39 Int. 7.02 7.43 7.43 6.31 6.5 5.29 <5 ~5.53 <5 <5 <5 <5 <5 5.04 8 188.56 8.6 8.9 8.32 6.94 6.88 <5 7.22 <5 5.01 <5 <5 <5 6.57 27 8.785 8.258.625 8.505 7.425 8.715 5.16 8.22 <5 5.335 <5 <5 <5 8.18 19 7.96 7.948.25 7.22 7 6.32 <5 6.26 <5 5.1 <5 6.03 <5 5.71 24 8.73 8.31 ~8.96 8.16.54 7.73 <5 ~7.67 <5 5.05 <5 <5 <5 6.6 25 7.91 7.71 8.23 7.22 6.23 6.57<5 6.76 <5 <5 <5 <5 <5 6.07 22 8.92 8.41 8.62 8.36 7.36 7.85 5.05 7.78<5 5.79 <5 5.22 <5 ~7.11 21 8.83 8.59 8.47 8.27 6.99 7.55 <5 7.57 <55.49 <5 5.09 <5 6.79 14 9.13 8.28 8.46 8.13 7.02 7.2 <5 ~6.95 <5 5.45 <5<5 <5 6.7 13 8.6 8.18 8.31 8.06 6.89 7.23 <5 7 <5 5.57 <5 6.81 2 8.888.49 8.41 8.4 7.59 8.3 5.09 7.86 <5 6.18 <5 5.34 <5 7.83 26 8.32 7.988.31 7.9 6.37 7.95 5.12 8.17 <5 5.11 <5 5.16 ~5 7.77 47 8.93 8.41 8.888.66 7.93 ~8.03 <5 8.46 <5 6.44 <5 5.14 <5 7.44 42 8.94 8.50 8.47 8.547.80 8.95 5.25 8.25 <5 6.95 <5 5.70 <5 8.25 48 8.08 7.84 8.10 7.50 6.547.24 5.13 7.62 <5 5.02 <5 5.23 <5 7.17 43 8.97 8.61 8.62 8.58 7.83 8.685.05 ~8 <5 6.51 <5 5.24 <5 ~8.02 44 8.24 8.49 8.77 ~7.87 7.28 5.65 <56.61 <5 5.18 <5 — — 6.00  48a 6.53 6.77 6.38 6.08 <6 <5 <5 <5 <5 <5 <5 —— <5 46 8.20 8.44 8.61 7.77 5.99 5.89 <5 5.68 <5 <5 <5 — — 5.28 50 7.167.26 7.24 6.59 <6 5.11 <5 5.19 <5 <5 <5 — — <5 51 8.56 8.40 8.10 7.866.77 6.13 <5 5.82 <5 5.15 ~5.22 — — 5.87 52 7.80 8.18 8.07 7.78 6.035.77 <5 6.00 <5 <5 <5 — — 5.48 54 6.42 6.74 6.84 <6 <6 <5 <5 5.16 <5 <5<5 — — <5 55 7.04 7.7 7.69 6.88 <6 5.64 <5 5.77 <5 <5 <5 — — 5.37 578.55 8.64 8.98 8.35 6.34 6.75 <5 ~6.77 <5 <5 <5 <5 <5 6.16 58 8.03 7.897.56 6.73 6.14 ~5.86 <5 5.57 <5 <5 <5 <5 <5 <5 59 8.33 8.52 8.76 8.136.07 6.36 <5 6.50 <5 <5 <5 <5 <5 6.02 60 7.94 7.71 7.50 6.60 <6 5.37 <55.22 <5 <5 <5 <5 <5 <5 31 7.66 7.51 7.73 6.59 6.8 5.65 <5 5.46 <5 <5 <5— — 5.12 62 8.53 8.68 8.84 8.48 6.59 6.63 <5 6.75 <5 <5 <5 6.24 61 7.85~7.90 8.57 7.68 6.72 6.02 ~5.02 5.84 <5 5.40 <5 5.66 30 7.67 7.46 7.666.52 6.48 6.03 5.16 5.89 5.18 5.55 <5 5.25 41 7.63 7.69 7.41 6.78 <66.43 <5 6.30 <5 <5 <5 5.78 29 7.27 ~7.17 7.34 6.25 5.45 <5 5.29 <5 5.15<5 <5 39 6.77 6.55 6.75 <6 <6 5.09 <5 <5 <5 <5 <5 <5 40 6.73 6.52 6.66<6 <5 <5 5.08 <5 <5 <5 <5 34 6.71 6.73 7.67 6.38 <6 5.01 <5 5.16 <5 <5<5 <5 36 <6 <6 <6 <6 <6

The invention claimed is:
 1. A method for treating a subject sufferingfrom, or being at risk of suffering from a disease state or conditionmediated by a FGFR kinase, said method comprising administering to thesubject a compound selected from the group consisting of a compound offormula (I):

a tautomeric form and stereochemically isomeric form thereof, wherein Wis —N(R³)— or —C(R^(3a)R^(3b))—; each R² is independently selected fromhydroxyl, halogen, cyano, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄alkoxy, hydroxyC₁₋₄alkyl, hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl,haloC₁₋₄alkoxy, hydroxyhaloC₁₋₄alkyl, hydroxyhaloC₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl, haloC₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkylwherein each C₁₋₄alkyl may optionally be substituted with one or twohydroxyl groups, hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkyl substitutedwith —NR⁷R⁸, C₁₋₄alkyl substituted with —C(═O)—NR⁷R⁸, C₁₋₄alkoxysubstituted with —NR⁷R⁸, C₁₋₄alkoxy substituted with —C(═O)—NR⁷R⁸,—NR⁷R⁸ and —C(═O)—NR⁷R⁸; Y represents -E-D; D represents a 3, 4, 5, 6, 7or 8 membered monocyclic carbocyclyl or a 3, 4, 5, 6, 7 or 8 memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O and S, wherein said carbocyclyl and heterocyclyl may each beoptionally substituted by one or more R¹ groups; E represents a bond; R¹represents hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,—C(═O)—O—C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups,—NR⁴R⁵, C₁₋₆alkyl substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —NR⁴R⁵, —C(═O)—NR⁴R⁵, —C(═O)—C₁₋₆alkyl-NR⁴R⁵, C₁₋₆alkylsubstituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl,—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted withR⁶, —C(═O)—R⁶, C₁₋₆alkyl substituted with —C(═O)—R⁶, hydroxyC₁₋₆alkylsubstituted with R⁶, C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkylsubstituted with —P(═O)(OH)₂ or C₁₋₆alkyl substituted with—P(═O)(OC₁₋₆alkyl)₂; R^(3a) represents —NR¹⁰R¹¹, hydroxyl, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxy substituted with —NR¹⁰R¹¹, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, haloC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted withcarboxyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R^(3b) representshydrogen or hydroxyl; provided that if R^(3a) represents —NR¹⁰R¹¹, thenR^(3b) represents hydrogen; or R^(3a) and R^(3b) are taken together toform ═O, to form ═NR¹⁰, to form cyclopropyl together with the carbonatom to which they are attached, to form ═CH—C₀₋₄alkyl substituted withR^(3c), or to form

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining one heteroatom selected from N, O and S, said heteroatom notbeing positioned in alpha position of the double bond, wherein ring A isoptionally being substituted with cyano, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,H₂N—C₁₋₄alkyl, (C₁₋₄alkyl)NH—C₁₋₄alkyl, (C₁₋₄alkyl)₂N—C₁₋₄alkyl,haloC₁₋₄alkyl)NH—C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, —C(═O)—NH₂,—C(═O)—NH(C₁₋₄alkyl), —C(═O)—N(C₁₋₄alkyl)₂; R^(3c) represents hydrogen,hydroxyl, C₁₋₆alkoxy, R⁹, —NR¹⁰R¹¹, cyano, —C(═O)—C₁₋₆alkyl or—CH(OH)—C₁₋₆alkyl; R³ represents hydroxyl, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxy substituted with —NR¹⁰R¹¹, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, haloC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted withcarboxyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R⁴ and R⁵ eachindependently represent hydrogen, C₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹⁴R¹⁵, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵,—C(═O)—O—C₁₋₆alkyl, —C(═O)—R¹³, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³ or C₁₋₆alkyl substituted with R¹³; R⁶ represents C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclylcontaining at least one heteroatom selected from N, O and S; saidC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclicheterocyclyl, optionally and each independently being substituted by 1,2, 3, 4 or 5 substituents, each substituent independently being selectedfrom cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyl, carboxyl,hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵,—C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl and C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R⁷ and R⁸ each independently represent hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl orC₁₋₆alkoxyC₁₋₆alkyl; R⁹ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,phenyl, or 3, 4, 5, 6, 7 or 8 membered monocyclic heterocyclylcontaining at least one heteroatom selected from N, O and S, saidC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, or 3, 4, 5, 6, 7 or 8 memberedmonocyclic heterocyclyl each optionally and each independently beingsubstituted with 1, 2, 3, 4 or 5 substituents, each substituentindependently being selected from ═O, C₁₋₄alkyl, hydroxyl, carboxyl,hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkylsubstituted with C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkyl-C(═O)—,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl may optionally be substitutedwith one or two hydroxyl groups, halogen, haloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkyl substitutedwith —NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkylsubstituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with—NH—S(═O)₂—C₁₋₄alkyl, C₁₋₄alkyl substituted with—NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with R¹³, phenyl optionallysubstituted with R¹⁶ phenylC₁₋₆alkyl wherein the phenyl is optionallysubstituted with R¹⁶, a 5 or 6-membered aromatic monocyclic heterocyclylcontaining at least one heteroatom selected from N, O and S wherein saidheterocyclyl is optionally substituted with R¹⁶; R¹⁰ and R¹¹ eachindependently represent hydrogen, carboxyl, C₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—C(═O)—NR¹⁴R¹⁵, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally besubstituted with one or two hydroxyl groups, R⁶, C₁₋₆alkyl substitutedwith R⁶, —C(═O)—R⁶, —C(═O)—C₁₋₆alkyl, —C(═O)-hydroxyC₁₋₆alkyl,—C(═O)-haloC₁₋₆alkyl, —C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substitutedwith —Si(CH₃)₃, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl,—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with carboxyl, or C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R¹² represents hydrogen or C₁₋₄alkyl optionallysubstituted with C₁₋₄alkoxy; R¹³ represents C₃₋₈cycloalkyl or asaturated 4 to 6-membered monocyclic heterocyclyl containing at leastone heteroatom selected from N, O and S, wherein said C₃₋₈cycloalkyl ormonocyclic heterocyclyl is optionally substituted with 1, 2 or 3substituents each independently selected from halogen, hydroxyl,C₁₋₆alkyl, haloC₁₋₆alkyl, ═O, cyano, —C(═O)—C₁₋₆alkyl, C₁₋₆alkoxy, and—NR¹⁴R¹⁵; R¹⁴ and R¹⁵ each independently represent hydrogen, orhaloC₁₋₄alkyl, or C₁₋₄alkyl optionally substituted with a substituentselected from hydroxyl, C₁₋₄alkoxy, amino and mono- ordi(C₁₋₄alkyl)amino; R¹⁶ represents hydroxyl, halogen, cyano, C₁₋₄alkyl,C₁₋₄alkoxy, —NR¹⁴R¹⁵ or —C(═O)NR¹⁴R¹⁵; and n independently represents aninteger equal to 0, 1, 2, 3 or 4; or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof, whereinthe disease state or condition mediated by a FGFR kinase is selectedfrom cancer and proliferative disorders.
 2. A method according to claim1 wherein the compound is selected from the group consisting of acompound of formula (I), a tautomeric form, and stereochemicallyisomeric form thereof, wherein D is: (i) optionally substitutedpyrazolyl; or (ii) piperidinyl, pyridinyl, phenyl, pyrolyl, imidazolyl,triazolyl, thiazolyl, cyclopentyl, azetidinyl, morpholinyl, tetrazolyl,oxazolyl, piperazinyl, 1,2,3,6-tetrahydropyridinyl, 2,5-dihydropyrolyl,pyrimidinyl, pyrolidinyl, said rings being optionally substituted, or anN-oxide thereof, a pharmaceutically acceptable salt thereof or a solvatethereof.
 3. A method according to claim 1 wherein the compound isselected from the group consisting of a compound of formula (I), atautomeric form, and stereochemically isomeric form thereof, wherein Wis —N(R³)—, or an N-oxide thereof, a pharmaceutically acceptable saltthereof or a solvate thereof.
 4. A method according to claim 1 whereinthe compound is selected from the group consisting of a compound offormula (I), a tautomeric form, and stereochemically isomeric formthereof, wherein W is —C(R^(3a)R^(3b))—, or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 5. Amethod according to claim 1 wherein the compound is selected from thegroup consisting of a compound of formula (I), a tautomeric form, andstereochemically isomeric form thereof, wherein R¹ represents C₁₋₆alkyl,or an N-oxide thereof, a pharmaceutically acceptable salt thereof or asolvate thereof.
 6. A method according to claim 1 wherein the compoundis selected from the group consisting of a compound of formula (I), atautomeric form, and stereochemically isomeric form thereof, wherein R²:(i) is independently selected from hydroxyl, halogen, cyano, C₁₋₄alkyl,C₂₋₄alkenyl, C₁₋₄alkoxy, hydroxyC₁₋₄alkyl, hydroxyC₁₋₄alkoxy,haloC₁₋₄alkoxy, C₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkyl substituted with NR⁷R⁸,C₁₋₄alkoxy substituted with NR⁷R⁸, —NR⁷R⁸ and —C(═O)—NR⁷R⁸; or (ii)represents C₁₋₄alkoxy; or (iii) represents C₁₋₄alkoxy or halogen, or anN-oxide thereof, a pharmaceutically acceptable salt thereof or a solvatethereof.
 7. A method according to claim 1 wherein the compound isselected from the group consisting of a compound of formula (I), atautomeric form, and stereochemically isomeric form thereof, wherein R³represents: (i) C₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, C₁₋₆alkyl substituted with R⁹,C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted with hydroxyland —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogens and—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —O—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with carboxyl,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NR¹²—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with hydroxyl and R⁹,—C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with —C(═O)—NR¹⁰R¹¹,C₁₋₆alkyl substituted with —C(═O)—R⁹, C₂₋₆alkynyl substituted with R⁹,hydroxyC₁₋₆alkoxy, C₂₋₆alkenyl, C₂₋₆alkynyl or R¹³; or (ii)hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹,C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₂₋₆alkynyl substituted with R⁹, orC₂₋₆alkynyl, or an N-oxide thereof, a pharmaceutically acceptable saltthereof or a solvate thereof.
 8. A method according to claim 1 whereinthe compound is selected from the group consisting of a compound offormula (I), a tautomeric form, and stereochemically isomeric formthereof, wherein R^(3a) represents hydroxyl, C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—O—C₁₋₆alkyl, or an N-oxide thereof, a pharmaceuticallyacceptable salt thereof or a solvate thereof.
 9. A method according toclaim 1 wherein the compound is selected from the group consisting of acompound of formula (I), a tautomeric form, and stereochemicallyisomeric form thereof, wherein R^(3b) represents hydrogen, or an N-oxidethereof, a pharmaceutically acceptable salt thereof or a solvatethereof.
 10. A method according to claim 1 wherein the compound isselected from the group consisting of a compound of formula (I), atautomeric form, and stereochemically isomeric form thereof, wherein:(i) n represents an integer equal to 2, 3 or 4; R² represents C₁₋₄alkoxyor halo; R³ represents hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkylsubstituted with R⁹, C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₂₋₆alkynylsubstituted with R⁹, or C₂₋₆alkynyl; D represents pyrazolyl, optionallysubstituted with C₁₋₆alkyl, hydroxyC₁₋₆alkyl or R⁶; W is —N(R³)— or—C(R^(3a)R^(3b))— wherein R^(3a) is hydroxyl, R^(3b) is hydrogen; or(ii) n represents an integer equal to 2, 3 or 4; R² representsC₁₋₄alkoxy or halogen; R³ represents hydroxyC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkynyl substituted with R⁹ orC₂₋₆alkynyl; R^(3a) represents hydroxyl, C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—O—C₁₋₆alkyl; R^(3b) represents hydrogen; or R^(3a) andR^(3b) are taken together to form ═O or to form ═CH—C₀₋₄alkylsubstituted with R^(3c); D represents an optionally substituted 5membered heterocycle, an optionally substituted 6 membered heterocycleor phenyl, or an N-oxide thereof, a pharmaceutically acceptable saltthereof or a solvate thereof.
 11. A method according to claim 1 whereinthe compound is selected from the group consisting of a compound offormula (I), a tautomeric form, and stereochemically isomeric formthereof; or a pharmaceutically acceptable salt or solvate thereof.
 12. Amethod for treating a subject suffering from, or being at risk ofsuffering from cancer, said method comprising administering to thesubject a compound selected from the group consisting of a compound offormula (I):

a tautomeric form and stereochemically isomeric form thereof, wherein Wis —N(R³)— or —C(R^(3a)R^(3b))—; each R² is independently selected fromhydroxyl, halogen, cyano, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄alkoxy, hydroxyC₁₋₄alkyl, hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl,haloC₁₋₄alkoxy, hydroxyhaloC₁₋₄alkyl, hydroxyhaloC₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl, haloC₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkylwherein each C₁₋₄alkyl may optionally be substituted with one or twohydroxyl groups, hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkyl substitutedwith —NR⁷R⁸, C₁₋₄alkyl substituted with —C(═O)—NR⁷R⁸, C₁₋₄alkoxysubstituted with —NR⁷R⁸, C₁₋₄alkoxy substituted with —C(═O)—NR⁷R⁸,—NR⁷R⁸ and —C(═O)—NR⁷R⁸; Y represents -E-D; D represents a 3, 4, 5, 6, 7or 8 membered monocyclic carbocyclyl or a 3, 4, 5, 6, 7 or 8 memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O and S, wherein said carbocyclyl and heterocyclyl may each beoptionally substituted by one or more R¹ groups; E represents a bond; R¹represents hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,—C(═O)—O—C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups,—NR⁴R⁵, C₁₋₆alkyl substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —NR⁴R⁵, —C(═O)—NR⁴R⁵, —C(═O)—C₁₋₆alkyl-NR⁴R⁵, C₁₋₆alkylsubstituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl,—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted withR⁶, —C(═O)—R⁶, C₁₋₆alkyl substituted with —C(═O)—R⁶, hydroxyC₁₋₆alkylsubstituted with R⁶, C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkylsubstituted with —P(═O)(OH)₂ or C₁₋₆alkyl substituted with—P(═O)(OC₁₋₆alkyl)₂; R^(3a) represents —NR¹⁰R¹¹, hydroxyl, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxy substituted with —NR¹⁰R¹¹, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, haloC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted withcarboxyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R^(3b) representshydrogen or hydroxyl; provided that if R^(3a) represents —NR¹⁰R¹¹, thenR^(3b) represents hydrogen; or R^(3a) and R^(3b) are taken together toform ═O, to form ═NR¹⁰, to form cyclopropyl together with the carbonatom to which they are attached, to form ═CH—C₀₋₄alkyl substituted withR^(3c), or to form

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining one heteroatom selected from N, O and S, said heteroatom notbeing positioned in alpha position of the double bond, wherein ring A isoptionally being substituted with cyano, C₁₋₄alkyl, hydroxyC₁₋₄alkyl,H₂N—C₁₋₄alkyl, (C₁₋₄alkyl)NH—C₁₋₄alkyl, (C₁₋₄alkyl)₂N—C₁₋₄alkyl,haloC₁₋₄alkyl)NH—C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, —C(═O)—NH₂,—C(═O)—NH(C₁₋₄alkyl), —C(═O)—N(C₁₋₄alkyl)₂; R^(3c) represents hydrogen,hydroxyl, C₁₋₆alkoxy, R⁹, —NR¹⁰R¹¹, cyano, —C(═O)—C₁₋₆alkyl or—CH(OH)—C₁₋₆alkyl; R³ represents hydroxyl, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxy substituted with —NR¹⁰R¹¹, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, haloC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted withcarboxyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R⁴ and R⁵ eachindependently represent hydrogen, C₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹⁴R¹⁵, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵,—C(═O)—O—C₁₋₆alkyl, —C(═O)—R¹³, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³ or C₁₋₆alkyl substituted with R¹³; R⁶ represents C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclylcontaining at least one heteroatom selected from N, O and S; saidC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclicheterocyclyl, optionally and each independently being substituted by 1,2, 3, 4 or 5 substituents, each substituent independently being selectedfrom cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyl, carboxyl,hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵,—C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl and C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R⁷ and R⁸ each independently represent hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl orC₁₋₆alkoxyC₁₋₆alkyl; R⁹ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,phenyl, or 3, 4, 5, 6, 7 or 8 membered monocyclic heterocyclylcontaining at least one heteroatom selected from N, O and S, saidC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, or 3, 4, 5, 6, 7 or 8 memberedmonocyclic heterocyclyl each optionally and each independently beingsubstituted with 1, 2, 3, 4 or 5 substituents, each substituentindependently being selected from ═O, C₁₋₄alkyl, hydroxyl, carboxyl,hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkylsubstituted with C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkyl-C(═O)—,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl may optionally be substitutedwith one or two hydroxyl groups, halogen, haloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkyl substitutedwith —NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkylsubstituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with—NH—S(═O)₂—C₁₋₄alkyl, C₁₋₄alkyl substituted with—NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with R¹³, phenyl optionallysubstituted with R¹⁶ phenylC₁₋₆alkyl wherein the phenyl is optionallysubstituted with R¹⁶, a 5 or 6-membered aromatic monocyclic heterocyclylcontaining at least one heteroatom selected from N, O and S wherein saidheterocyclyl is optionally substituted with R¹⁶; R¹⁰ and R¹¹ eachindependently represent hydrogen, carboxyl, C₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—C(═O)—NR¹⁴R¹⁵, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally besubstituted with one or two hydroxyl groups, R⁶, C₁₋₆alkyl substitutedwith R⁶, —C(═O)—R⁶, —C(═O)—C₁₋₆alkyl, —C(═O)-hydroxyC₁₋₆alkyl,—C(═O)-haloC₁₋₆alkyl, —C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substitutedwith —Si(CH₃)₃, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl,—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with carboxyl, or C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R¹² represents hydrogen or C₁₋₄alkyl optionallysubstituted with C₁₋₄alkoxy; R¹³ represents C₃₋₈cycloalkyl or asaturated 4 to 6-membered monocyclic heterocyclyl containing at leastone heteroatom selected from N, O and S, wherein said C₃₋₈cycloalkyl ormonocyclic heterocyclyl is optionally substituted with 1, 2 or 3substituents each independently selected from halogen, hydroxyl,C₁₋₆alkyl, haloC₁₋₆alkyl, ═O, cyano, —C(═O)—C₁₋₆alkyl, C₁₋₆alkoxy, and—NR¹⁴R¹⁵; R¹⁴ and R¹⁵ each independently represent hydrogen, orhaloC₁₋₄alkyl, or C₁₋₄alkyl optionally substituted with a substituentselected from hydroxyl, C₁₋₄alkoxy, amino and mono- ordi(C₁₋₄alkyl)amino; R¹⁶ represents hydroxyl, halogen, cyano, C₁₋₄alkyl,C₁₋₄alkoxy, —NR¹⁴R¹⁵ or —C(═O)NR¹⁴R¹⁵; and n independently represents aninteger equal to 0, 1, 2, 3 or 4; or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 13. Amethod according to claim 12, wherein the cancer is selected frommultiple myeloma, myeloproliferative disorders, endometrial cancer,prostate cancer, bladder cancer, lung cancer, ovarian cancer, breastcancer, gastric cancer, colorectal cancer, and oral squamous cellcarcinoma.
 14. A method according to claim 12, wherein the cancer isselected from lung cancer, squamous cell carcinoma, liver cancer, kidneycancer, breast cancer, colon cancer, colorectal cancer, and prostatecancer.
 15. A method according to claim 13, wherein the cancer ismultiple myeloma.
 16. A method according to claim 13, wherein the canceris bladder cancer.
 17. A method according to claim 12, wherein thecancer is urothelial carcinoma.
 18. A method for treating a subjectsuffering from, or being at risk of suffering from a carcinoma, whereinthe carcinoma is selected from a carcinoma of the bladder, breast,colon, kidney, epidermis, liver, lung, oesophagus, head and neck, gallbladder, ovary, pancreas, stomach, gastrointestinal (also known asgastric) cancer, cervix, endometrium, thyroid, prostate, or skin, ahematopoietic tumour of lymphoid lineage; a hematopoietic tumour ofmyeloid lineage; multiple myeloma; thyroid follicular cancer; a tumourof mesenchymal origin; a tumour of the central or peripheral nervoussystem; melanoma; seminoma; teratocarcinoma; osteosarcoma; xerodermapigmentosum; keratoctanthoma; or Kaposi's sarcoma, said methodcomprising administering to the subject a compound selected from thegroup consisting of a compound of formula (I):

a tautomeric form and stereochemically isomeric form thereof, wherein Wis —N(R³)— or —C(R^(3a)R^(3b))—; each R² is independently selected fromhydroxyl, halogen, cyano, C₁₋₄alkyl, C₂₋₄alkenyl, C₂₋₄alkynyl,C₁₋₄alkoxy, hydroxyC₁₋₄alkyl, hydroxyC₁₋₄alkoxy, haloC₁₋₄alkyl,haloC₁₋₄alkoxy, hydroxyhaloC₁₋₄alkyl, hydroxyhaloC₁₋₄alkoxy,C₁₋₄alkoxyC₁₋₄alkyl, haloC₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkylwherein each C₁₋₄alkyl may optionally be substituted with one or twohydroxyl groups, hydroxyhaloC₁₋₄alkoxyC₁₋₄alkyl, C₁₋₄alkyl substitutedwith —NR⁷R⁸, C₁₋₄alkyl substituted with —C(═O)—NR⁷R⁸, C₁₋₄alkoxysubstituted with —NR⁷R⁸, C₁₋₄alkoxy substituted with —C(═O)—NR⁷R⁸,—NR⁷R⁸ and —C(═O)—NR⁷R⁸; Y represents -E-D; D represents a 3, 4, 5, 6, 7or 8 membered monocyclic carbocyclyl or a 3, 4, 5, 6, 7 or 8 memberedmonocyclic heterocyclyl containing at least one heteroatom selected fromN, O and S, wherein said carbocyclyl and heterocyclyl may each beoptionally substituted by one or more R¹ groups; E represents a bond; R¹represents hydrogen, halo, cyano, C₁₋₆alkyl, C₁₋₆alkoxy,—C(═O)—O—C₁₋₆alkyl, C₂₋₄alkenyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₄alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein eachC₁₋₆alkyl may optionally be substituted with one or two hydroxyl groups,—NR⁴R⁵, C₁₋₆alkyl substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —NR⁴R⁵, —C(═O)—NR⁴R⁵, —C(═O)—C₁₋₆alkyl-NR⁴R⁵, C₁₋₆alkylsubstituted with —C(═O)—NR⁴R⁵, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl,—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with —NR¹²—S(═O)₂—NR¹⁴R¹⁵, R⁶, C₁₋₆alkyl substituted withR⁶, —C(═O)—R⁶, C₁₋₆alkyl substituted with —C(═O)—R⁶, hydroxyC₁₋₆alkylsubstituted with R⁶, C₁₋₆alkyl substituted with —Si(CH₃)₃, C₁₋₆alkylsubstituted with —P(═O)(OH)₂ or C₁₋₆alkyl substituted with—P(═O)(OC₁₋₆alkyl)₂; R^(3a) represents —NR¹⁰R¹¹, hydroxyl, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxy substituted with —NR¹⁰R¹¹, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, haloC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted withcarboxyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R^(3b) representshydrogen or hydroxyl; provided that if R^(3a) represents —NR¹⁰R¹¹, thenR^(3b) represents hydrogen; or R^(3a) and R^(3b) are taken together toform ═O, to form ═NR¹⁰, to form cyclopropyl together with the carbonatom to which they are attached, to form ═CH—C₀₋₄alkyl substituted withR^(3c), or to form

wherein ring A is a monocyclic 5 to 7 membered saturated heterocyclecontaining of the double bond, wherein ring A is optionally beingsubstituted with cyano, C₁₋₄alkyl, hydroxyC₁₋₄alkyl, H₂N—C₁₋₄alkyl,(C₁₋₄alkyl)NH—C₁₋₄alkyl, (C₁₋₄alkyl)₂N—C₁₋₄alkyl,haloC₁₋₄alkyl)NH—C₁₋₄alkyl, C₁₋₄alkoxyC₁₋₄alkyl, —C(═O)—NH₂,—C(═O)—NH(C₁₋₄alkyl), —C(═O)—N(C₁₋₄alkyl)₂; R^(3c) represents hydrogen,hydroxyl, C₁₋₆alkoxy, R⁹, —NR¹⁰R¹¹, cyano, —C(═O)—C₁₋₆alkyl or—CH(OH)—C₁₋₆alkyl; R³ represents hydroxyl, C₁₋₆alkoxy,hydroxyC₁₋₆alkoxy, C₁₋₆alkoxy substituted with —NR¹⁰R¹¹, C₁₋₆alkyl,C₂₋₆alkenyl, C₂₋₆alkynyl, haloC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₁₋₆alkyl optionally substituted with—O—C(═O)—C₁₋₆alkyl, hydroxyC₂₋₆alkenyl, hydroxyC₂₋₆alkynyl,hydroxyhaloC₁₋₆alkyl, cyanoC₁₋₆alkyl, C₁₋₆alkyl substituted withcarboxyl, C₁₋₆alkyl substituted with —C(═O)—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —C(═O)—O—C₁₋₆alkyl, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-O—C(═O)—, C₁₋₆alkyl substituted withC₁₋₆alkoxyC₁₋₆alkyl-C(═O)—, C₁₋₆alkyl substituted with—O—C(═O)—C₁₋₆alkyl, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl mayoptionally be substituted with one or two hydroxyl groups or with—O—C(═O)—C₁₋₆alkyl, C₂₋₆alkenyl substituted with C₁₋₆alkoxy, C₂₋₆alkynylsubstituted with C₁₋₆alkoxy, C₁₋₆alkyl substituted with R⁹ andoptionally substituted with —O—C(═O)—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—R⁹, C₁₋₆alkyl substituted with hydroxyl and R⁹, C₂₋₆alkenylsubstituted with R⁹, C₂₋₆alkynyl substituted with R⁹, C₁₋₆alkylsubstituted with —NR¹⁰R¹¹, C₂₋₆alkenyl substituted with —NR¹⁰R¹¹,C₂₋₆alkynyl substituted with —NR¹⁰R¹¹, C₁₋₆alkyl substituted withhydroxyl and —NR¹⁰R¹¹, C₁₋₆alkyl substituted with one or two halogensand —NR¹⁰R¹¹, —C₁₋₆alkyl-C(R¹²)═N—O—R¹², C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, C₁₋₆alkyl substituted with —O—C(═O)—NR¹⁰R¹¹,—S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵,C₁₋₆alkyl substituted with —NR¹²—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substitutedwith —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹²—S(═O)₂—NR¹⁴R¹⁵, R¹³, C₁₋₆alkyl substituted with —P(═O)(OH)₂ orC₁₋₆alkyl substituted with —P(═O)(OC₁₋₆alkyl)₂; R⁴ and R⁵ eachindependently represent hydrogen, C₁₋₆alkyl, C₁₋₆alkyl substituted with—NR¹⁴R¹⁵, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally be substitutedwith one or two hydroxyl groups, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵,—C(═O)—O—C₁₋₆alkyl, —C(═O)—R¹³, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³ or C₁₋₆alkyl substituted with R¹³; R⁶ represents C₃₋₈cycloalkyl,C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclic heterocyclylcontaining at least one heteroatom selected from N, O and S; saidC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, 4 to 7-membered monocyclicheterocyclyl, optionally and each independently being substituted by 1,2, 3, 4 or 5 substituents, each substituent independently being selectedfrom cyano, C₁₋₆alkyl, cyanoC₁₋₆alkyl, hydroxyl, carboxyl,hydroxyC₁₋₆alkyl, halogen, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl, C₁₋₆alkyl-O—C(═O)—, —NR¹⁴R¹⁵,—C(═O)—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkylsubstituted with —C(═O)—NR¹⁴R¹⁵, —S(═O)₂—C₁₋₆alkyl,—S(═O)₂-haloC₁₋₆alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂-haloC₁₋₆alkyl,C₁₋₆alkyl substituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—NH—S(═O)₂—C₁₋₆alkyl, C₁₋₆alkyl substituted with—NH—S(═O)₂-haloC₁₋₆alkyl and C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R⁷ and R⁸ each independently represent hydrogen,C₁₋₆alkyl, hydroxyC₁₋₆alkyl, haloC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl orC₁₋₆alkoxyC₁₋₆alkyl; R⁹ represents C₃₋₈cycloalkyl, C₃₋₈cycloalkenyl,phenyl, or 3, 4, 5, 6, 7 or 8 membered monocyclic heterocyclylcontaining at least one heteroatom selected from N, O and S, saidC₃₋₈cycloalkyl, C₃₋₈cycloalkenyl, phenyl, or 3, 4, 5, 6, 7 or 8 memberedmonocyclic heterocyclyl each optionally and each independently beingsubstituted with 1, 2, 3, 4 or 5 substituents, each substituentindependently being selected from ═O, C₁₋₄alkyl, hydroxyl, carboxyl,hydroxyC₁₋₄alkyl, cyano, cyanoC₁₋₄alkyl, C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkylsubstituted with C₁₋₄alkyl-O—C(═O)—, C₁₋₄alkyl-C(═O)—,C₁₋₄alkoxyC₁₋₄alkyl wherein each C₁₋₄alkyl may optionally be substitutedwith one or two hydroxyl groups, halogen, haloC₁₋₄alkyl,hydroxyhaloC₁₋₄alkyl, —NR¹⁴R¹⁵, —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkyl substitutedwith —NR¹⁴R¹⁵, C₁₋₄alkyl substituted with —C(═O)—NR¹⁴R¹⁵, C₁₋₄alkoxy,—S(═O)₂—C₁₋₄alkyl, —S(═O)₂-haloC₁₋₄alkyl, —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkylsubstituted with —S(═O)₂—NR¹⁴R¹⁵, C₁₋₄alkyl substituted with—NH—S(═O)₂—C₁₋₄alkyl, C₁₋₄alkyl substituted with—NH—S(═O)₂-haloC₁₋₄alkyl, C₁₋₄alkyl substituted with —NH—S(═O)₂—NR¹⁴R¹⁵,R¹³, —C(═O)—R¹³, C₁₋₄alkyl substituted with R¹³, phenyl optionallysubstituted with R¹⁶ phenylC₁₋₆alkyl wherein the phenyl is optionallysubstituted with R¹⁶, a 5 or 6-membered aromatic monocyclic heterocyclylcontaining at least one heteroatom selected from N, O and S wherein saidheterocyclyl is optionally substituted with R¹⁶; R¹⁰ and R¹¹ eachindependently represent hydrogen, carboxyl, C₁₋₆alkyl, cyanoC₁₋₆alkyl,C₁₋₆alkyl substituted with —NR¹⁴R¹⁵, C₁₋₆alkyl substituted with—C(═O)—NR¹⁴R¹⁵, haloC₁₋₆alkyl, hydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl,C₁₋₆alkoxy, C₁₋₆alkoxyC₁₋₆alkyl wherein each C₁₋₆alkyl may optionally besubstituted with one or two hydroxyl groups, R⁶, C₁₋₆alkyl substitutedwith R⁶, —C(═O)—R⁶, —C(═O)—C₁₋₆alkyl, —C(═O)-hydroxyC₁₋₆alkyl,—C(═O)-haloC₁₋₆alkyl, —C(═O)-hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substitutedwith —Si(CH₃)₃, —S(═O)₂—C₁₋₆alkyl, —S(═O)₂-haloC₁₋₆alkyl,—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl, C₁₋₆alkylsubstituted with —S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkyl substituted with—S(═O)₂—NR¹⁴R¹⁵, C₁₋₆alkyl substituted with —NH—S(═O)₂—C₁₋₆alkyl,C₁₋₆alkyl substituted with —NH—S(═O)₂-haloC₁₋₆alkyl, C₁₋₆alkylsubstituted with carboxyl, or C₁₋₆alkyl substituted with—NH—S(═O)₂—NR¹⁴R¹⁵; R¹² represents hydrogen or C₁₋₄alkyl optionallysubstituted with C₁₋₄alkoxy; R¹³ represents C₃₋₈cycloalkyl or asaturated 4 to 6-membered monocyclic heterocyclyl containing at leastone heteroatom selected from N, O and S, wherein said C₃₋₈cycloalkyl ormonocyclic heterocyclyl is optionally substituted with 1, 2 or 3substituents each independently selected from halogen, hydroxyl,C₁₋₆alkyl, haloC₁₋₆alkyl, ═O, cyano, —C(═O)—C₁₋₆alkyl, C₁₋₆alkoxy, and—NR¹⁴R¹⁵; R¹⁴ and R¹⁵ each independently represent hydrogen, orhaloC₁₋₄alkyl, or C₁₋₄alkyl optionally substituted with a substituentselected from hydroxyl, C₁₋₄alkoxy, amino and mono- ordi(C₁₋₄alkyl)amino; R¹⁶ represents hydroxyl, halogen, cyano, C₁₋₄alkyl,C₁₋₄alkoxy, —NR¹⁴R¹⁵ or —C(═O)NR¹⁴R¹⁵; and n independently represents aninteger equal to 0, 1, 2, 3 or 4; or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 19. Amethod according to claim 10 wherein the compound is selected from thegroup consisting of a compound of formula (I), a tautomeric form, andstereochemically isomeric form thereof, wherein n represents an integerequal to 2, 3 or 4; R² represents C₁₋₄alkoxy or halogen; R³ representshydroxyC₁₋₆alkyl, hydroxyhaloC₁₋₆alkyl, C₁₋₆alkyl substituted with R⁹,C₁₋₆alkyl substituted with —NR¹⁰R¹¹, C₂₋₆alkynyl substituted with R⁹ orC₂₋₆alkynyl; R^(3a) represents hydroxyl, C₁₋₆alkyl substituted with—C(═O)—NR¹⁰R¹¹, cyanoC₁₋₆alkyl, hydroxyC₁₋₆alkyl, C₁₋₆alkyl substitutedwith —C(═O)—O—C₁₋₆alkyl; R^(3b) represents hydrogen; or R^(3a) andR^(3b) are taken together to form ═O or to form ═CH—C₀₋₄alkylsubstituted with R^(3c); D represents an optionally substituted aromatic5 membered heterocycle, an optionally substituted saturated, partiallysaturated or aromatic 6 membered heterocycle, or phenyl, or an N-oxidethereof, a pharmaceutically acceptable salt thereof or a solvatethereof.
 20. A method according to claim 19 wherein the compound isselected from the group consisting of a compound of formula (I), atautomeric form, and stereochemically isomeric form thereof, wherein Drepresents pyrazol-4-yl, optionally substituted with C₁₋₆alkyl,hydroxyC₁₋₆alkyl, C₁₋₆alkyl substituted with —S(═O)₂—C₁₋₆alkyl or R⁶, orphenyl, or pyridyl or morpholinyl or 1,2,3,6-tetrahydropyridyl orpyrrolyl optionally substituted with C₁₋₆alkyl, or an N-oxide thereof, apharmaceutically acceptable salt thereof or a solvate thereof.
 21. Amethod according to claim 1, wherein the disease or condition mediatedby a FGFR kinase is cancer.